bluuebunny/crossref_metadata_2025 huggingface dataset:
Personalized circuit modeling captures variation in cortical functional connectivity
Authors: Cooper Rachel A. , Demirtaş Murat , Burt Joshua B. , Howell Amber M. , Ji J. Lisa , Repovš Grega , Sotiropoulos Stamatios N. , Anticevic Alan , Murray John D.
Published: February 2024

Functional magnetic resonance imaging (fMRI) of the human cortex reveals patterns of correlated neural dynamics that are individual-specific and associated with phenotypic variation. However, circuit mechanisms underlying individual variation in functional connectivity (FC) are not well understood. Here, we fit individual-level FC patterns with a biophysically-based circuit model of large-scale cortical dynamics. This model is fit with a small number of neurophysiologically interpretable parameters, and incorporates a hierarchical gradient in local synaptic strengths across cortex parameterized via the structural MRI-derived T1w/T2w map. We applied our modeling framework to resting-state fMRI FC from a large cohort of subjects (N=842) from the Human Connectome Project. We found that the model captures a substantial portion of individual variation in FC, especially with personalized degrees of local synaptic specialization along the hierarchical gradient. Furthermore, the model can capture to the within-subject variation in FC across scans. Empirically, we found that principal modes of individual variation in FC follow interpretable topographic patterns. We developed a framework to assess model expressivity via how these empirical modes of FC variation align with variations in simulated FC induced by parameter perturbations. This framework reveals a straightforward mapping between key parameters and the leading modes of variation across subjects and provides a principled approach to extending computational models. Collectively, our modeling results establish a foundation for personalized computational modeling of functional dynamics in large-scale brain circuits.
Proteomic analysis of gut inLabeo rohitareveals ECM as Key Player in host’s Response toAeromonas hydrophilaInfection
Authors: Nissa Mehar Un , Pinto Nevil , Ghosh Biplab , Banerjee Anwesha , Singh Urvi , Goswami Mukunda , Srivastava Sanjeeva
Published: February 2024

In the aquaculture sector, one of the challenges include disease outbreaks such as bacterial infections, particularly fromAeromonas hydrophila(Ah), impacting both wild and farmed fish. In this study, we conducted a proteomic analysis of the gut tissue inLabeo rohitafollowingAhinfection to elucidate the protein alterations and its implications for immune response. Our findings reveal significant dysregulation in extracellular matrix (ECM) associated proteins duringAhinfection, with increased abundance of elastin and Collagen alpha-3(VI) contributing to matrix rigidity. Pathway and enrichment analysis of differentially expressed proteins (DEPs) highlights the involvement of ECM-related pathways, including Focal adhesions, Integrin cell surface interactions, and actin cytoskeleton organization.

Focal adhesions, crucial for connecting intracellular actin bundles to the ECM, play a pivotal role in immune response during infections. Increased abundance of integrin alpha 1, integrin beta 1, and Tetraspanin suggests their involvement in the host’s response toAhinfection. Proteins associated with actin cytoskeleton reorganization, such as myosin, tropomyosin, and phosphoglucomutase, exhibit increased abundance, influencing changes in cell behavior. Additionally, upregulated proteins like LTBP1 and Fibrillin-2 contribute to TGF-β signaling and focal adhesion, indicating their role in immune regulation.

The study also identifies elevated levels of laminin, galectin 3, and tenascin-C, which interact with integrins and other ECM components, influencing immune cell migration and function. These proteins, along with decorin and lumican, act as immunomodulators, coordinating pro- and anti-inflammatory responses. ECM fragments released during pathogen invasion serve as “danger signals,” initiating pathogen clearance and tissue repair through Toll-like receptor signaling.

IMPORTANCE

The study underscores the critical role of the extracellular matrix (ECM) and its associated proteins in the immune response of aquatic organisms during bacterial infections likeAeromonas hydrophila(Ah). Understanding the intricate interplay between ECM alterations and immune response pathways provides crucial insights for developing effective disease control strategies in aquaculture. By identifying key proteins and pathways involved in host defense mechanisms, this research lays the groundwork for targeted interventions to mitigate the impact of bacterial infections on fish health and aquaculture production.
Machine Learning Approaches in Label-Free Small Extracellular Vesicles Analysis with Surface-Enhanced Raman Scattering (SERS) for Cancer Diagnostics
Authors: Vang Der , Kelly Maria S. , Sheokand Manisha , Sharma Manju , Esfandiari Leyla , Dima Ruxandra I. , Strobbia Pietro
Published: February 2024

Early diagnosis remains of pivotal importance in reducing patient morbidity and mortality in cancer. To this end, liquid biopsy is emerging as a tool to perform broad cancer screenings. Small extracellular vesicles (sEVs), also called exosomes, found in bodily fluids can serve as important cancer biomarkers in these screenings. Our group has recently developed a label-free electrokinetic microchip to purify sEVs from blood. Herein, we demonstrate the feasibility to integrate this approach with surface-enhanced Raman scattering (SERS) analysis. SERS can be used to characterized extracted sEVs through their vibrational fingerprint that changes depending on the origin of sEVs. While these changes are not easily identified in spectra, they can be modeled with machine learning (ML) approaches. Common ML approaches in the field of spectral analysis use dimensionality reduction method that often function as a black box. To avoid this pitfall, we used Shapley additive explanations (SHAP) is a type of explainable AI (XAI) that bridges ML models and human comprehension by calculating the specific contribution of individual features to a model’s predictions, directly correlating model/decisions with the original data. Using these approaches we demonstrated a proof-of-concept model predictive of cancer from isolated sEVs, integrating the electrokinetic device and SERS. This work explores the use of explainable AI to perform diagnostic analysis on complex SERS data of clinical samples, while reporting interpretable biochemical information.
Molecular Architecture of Chitin and Chitosan-Dominated Cell Walls in Zygomycetous Fungal Pathogens by Solid-State NMR
Authors: Cheng Qinghui , Dickwella Widanage Malitha C. , Yarava Jayasubba Reddy , Latgé Jean-Paul , Wang Ping , Wang Tuo
Published: February 2024

Zygomycetous fungal infections pose an emerging medical threat among individuals with compromised immunity and metabolic abnormalities. Our pathophysiological understanding of these infections, particularly the role of fungal cell walls in growth and immune response, remains limited. Here we conducted multidimensional solid-state NMR analysis to examine cell walls in five Mucorales species, including key mucormycosis causative agents likeRhizopusandMucorspecies. We show that the rigid core of the cell wall primarily comprises highly polymorphic chitin and chitosan, with minimal quantities of β-glucans linked to a specific chitin subtype. Chitosan emerges as a pivotal molecule preserving hydration and dynamics. Some proteins are entrapped within this semi-crystalline chitin/chitosan layer, stabilized by the sidechains of hydrophobic amino acid residues, and situated distantly from β-glucans. The mobile domain contains galactan- and mannan-based polysaccharides, along with polymeric α-fucoses. Treatment with the chitin synthase inhibitor nikkomycin removes the β-glucan-chitin/chitosan complex, leaving the other chitin and chitosan allomorphs untouched while simultaneously thickening and rigidifying the cell wall. These findings shed light on the organization of Mucorales cell walls and emphasize the necessity for a deeper understanding of the diverse families of chitin synthases and deacetylases as potential targets for novel antifungal therapies.
Providing insight into the mechanism of action of Cationic Lipidated Oligomers (CLOs) using metabolomics
Authors: Hussein Maytham , Mahboob Muhammad Bilal Hassan , Tait Jessica R. , Grace James L. , Montembault Véronique , Fontaine Laurent , Quinn John F. , Velkov Tony , Whittaker Michael R. , Landersdorfer Cornelia B.
Published: February 2024

The increasing resistance of clinically relevant microbes against current commercially available antimicrobials underpins the urgent need for alternative and novel treatment strategies. Cationic lipidated oligomers (CLOs) are innovative alternatives to antimicrobial peptides, and have reported antimicrobial potential. An understanding of their antimicrobial mechanism of action is required to rationally design future treatment strategies for CLOs, either in monotherapy or synergistic combinations. In the present study, metabolomics was used to investigate the potential metabolic pathways involved in the mechanisms of antibacterial activity of one CLO, C12-o-(BG-D)-10, which we have previously shown to be effective against methicillin-resistantStaphylococcus aureus(MRSA) ATCC 43300. The metabolomes of MRSA ATCC 43300 at 1, 3 and 6 h following treatment with C12-o-(BG-D)-10 (48 µg/mL i.e., 3x MIC) were compared to those of the untreated controls.

Our findings reveal that the studied CLO, C12-o-(BG-D)-10, disorganized the bacterial membrane as the first step towards its antimicrobial effect, as evidenced by marked perturbations in the bacterial membrane lipids and peptidoglycan biosynthesis observed at early time points i.e., 1, and 3 h. Central carbon metabolism, and biosynthesis of DNA, RNA, and arginine were also vigorously perturbed, mainly at early time points. Moreover, bacterial cells were under osmotic and oxidative stress across all time points, evident by perturbations of trehalose biosynthesis and pentose phosphate shunt. Overall, this metabolomics study has, for the first time, revealed that the antimicrobial action of C12-o-(BG-D)-10 may potentially stem from the dysregulation of multiple metabolic pathways.

Importance

Antimicrobial resistance poses a significant challenge to healthcare systems worldwide. Novel anti-infective therapeutics are urgently needed to combat drug-resistant microorganisms. Cationic lipidated oligomers (CLOs) show promise as new antibacterial agents against Gram-positive pathogens likeStaphylococcus aureus(MRSA). Understanding their molecular mechanism(s) of antimicrobial action may help design synergistic CLO treatments along with monotherapy. Here, we describe the first metabolomics study to investigate the killing mechanism(s) of CLOs against MRSA. The results of our study indicate that the CLO, C12-o-(BG-D)-10, had a notable impact on the biosynthesis and organization of the bacterial cell envelope. C12-o-(BG-D)-10 also inhibits arginine, histidine, central carbon metabolism, and trehalose production, adding to its antibacterial characteristics. This work illuminates the unique mechanism of action of C12-o-(BG-D)-10 and opens an avenue to design innovative antibacterial oligomers/polymers for future clinical applications.
Habit learning shapes activity dynamics in the central nucleus of the amygdala
Authors: Amaya Kenneth A. , Carmichael J. Eric , Townsend Erica S. , Palmer Jensen A. , Stott Jeffrey J. , Smith Kyle S.
Published: February 2024

As animals perform instrumental tasks, they may develop a habit response with extended experience. Habits are automatic, inflexible, outcome value insensitive behaviors that are regulated by a network of brain regions including the central nucleus of the amygdala (CeA). Prior work has demonstrated that the CeA governs motivational pursuit and is necessary for habit formation. However, the behavioral features that CeA neurons encode in habit formation remain relatively unknown. To address this, we first used male and female Long-Evans rats to quantify CeA cFos expression after performance of a maze task. There, we found that animals with extended training show elevated cFos expression. Then, we implanted animals with drivable silicon probes to recordin-vivosingle unit electrophysiological activity from the CeA as animals developed habit responding on the maze. We observed significant activity during outcome consumption late in training while also observing elevated unit activity when animals consumed outcomes of larger magnitudes. Outcome related activity did not persist during probe tests following outcome devaluation, despite animals continuing to perform the task. Together, these data add to growing evidence that suggests that the CeA is involved in motivational processes that contribute to the development of habit formation.
Recurrent neural networks as neuro-computational models of human speech recognition
Authors: Brodbeck Christian , Hannagan Thomas , Magnuson James S.
Published: February 2024

Human speech recognition transforms a continuous acoustic signal into categorical linguistic units, by aggregating information that is distributed in time. It has been suggested that this kind of information processing may be understood through the computations of a Recurrent Neural Network (RNN) that receives input frame by frame, linearly in time, but builds an incremental representation of this input through a continually evolving internal state. While RNNs can simulate several keybehavioralobservations about human speech and language processing, it is unknown whether RNNs also develop computational dynamics that resemble humanneural speech processing. Here we show that the internal dynamics of long short-term memory (LSTM) RNNs, trained to recognize speech from auditory spectrograms, predict human neural population responses to the same stimuli, beyond predictions from auditory features. Variations in the RNN architecture motivated by cognitive principles further improve this predictive power. Moreover, different components of hierarchical RNNs predict separable components of brain responses to speech in an anatomically structured manner, suggesting that RNNs reproduce a hierarchy of speech recognition in the brain. Our results suggest that RNNs provide plausible computational models of the cortical processes supporting human speech recognition.
enmpa: An R package for ecological niche modeling using presence-absence data and generalized linear models
Authors: Arias-Giraldo Luis F. , Cobos Marlon E.
Published: February 2024

Here, we present the new R package “enmpa,” which includes a range of tools for modeling ecological niches using presence-absence data via logistic generalized linear models. The package allows users to calibrate, select, project, and evaluate models using independent data. We have emphasized a comprehensive search for ideal predictor combinations, including linear, quadratic, and two-way interaction responses, to provide more detailed and robust model calibration processes. We demonstrate the use of the package with an example of a simulated pathogen and its niche. Since enmpa is designed specifically to work with presence-absence data, our tools are particularly useful for studies with data derived from a detection or non-detection sampling universe, such as pathogen testing results. enmpa can be downloaded from CRAN, and the source code is freely available on GitHub.
Estradiol elicits distinct firing patterns in arcuate nucleus kisspeptin neurons of females through altering ion channel conductances
Authors: Qiu Jian , Voliotis Margaritis , Bosch Martha A. , Li Xiao Feng , Zweifel Larry S. , Tsaneva-Atanasova Krasimira , O’Byrne Kevin T. , Rønnekleiv Oline K. , Kelly Martin J.
Published: February 2024

Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1ARH) neurons are responsible for the pulsatile release of Gonadotropin-releasing Hormone (GnRH). In females, the behavior of Kiss1ARHneurons, expressing Kiss1, Neurokinin B (NKB), and Dynorphin (Dyn), varies throughout the ovarian cycle. Studies indicate that 17β-estradiol (E2) reduces peptide expression but increasesVglut2mRNA and glutamate neurotransmission in these neurons, suggesting a shift from peptidergic to glutamatergic signaling. To investigate this shift, we combined transcriptomics, electrophysiology, and mathematical modeling. Our results demonstrate that E2 treatment upregulates the mRNA expression of voltage-activated calcium channels, elevating the whole-cell calcium current and that contribute to high-frequency burst firing. Additionally, E2 treatment decreased the mRNA levels of Canonical Transient Receptor Potential (TPRC) 5 and G protein-coupled K+(GIRK) channels. When TRPC5 channels in Kiss1ARHneurons were deleted using CRISPR, the slow excitatory postsynaptic potential (sEPSP) was eliminated. Our data enabled us to formulate a biophysically realistic mathematical model of the Kiss1ARHneuron, suggesting that E2 modifies ionic conductances in Kiss1ARHneurons, enabling the transition from high frequency synchronous firing through NKB-driven activation of TRPC5 channels to a short bursting mode facilitating glutamate release. In a low E2 milieu, synchronous firing of Kiss1ARHneurons drives pulsatile release of GnRH, while the transition to burst firing with high, preovulatory levels of E2 would facilitate the GnRH surge through its glutamatergic synaptic connection to preoptic Kiss1 neurons.
Multi-modal Phantom Experiments, mimicking Flow through the Mitral Heart Valve
Authors: Christierson Lea , Frieberg Petter , Lala Tania , Töger Johannes , Liuba Petru , Revstedt Johan , Isaksson Hanna , Hakacova Nina
Published: February 2024

Purpose

Fluid-structure interaction (FSI) models are more commonly applied in medical research as computational power is increasing. However, understanding the accuracy of FSI models is crucial, especially in the context of heart valve disease in patient-specific models. Therefore, this study aimed to create a multi-modal benchmarking data set for FSI models, based on clinically important parameters, such as the pressure, velocity, and valve opening, with anin vitrophantom setup.

Method

Anin vitrosetup was developed with a 3D-printed phantom mimicking the left heart, including a deforming mitral valve. A range of pulsatile flows was created with a computer-controlled motor-and-pump setup. Invasive catheter measurements, magnetic resonance imaging (MRI), and echocardiography (Echo) imaging were used to measure pressure and velocity in the domain. Furthermore, the valve opening was quantified based on cine MRI and Echo images.

Result

The experimental setup, with 0.5 % cycle-to-cycle variation, was successfully built and six different flow cases were investigated. Higher velocity through the mitral valve was observed for increased cardiac output. The pressure difference across the valve also followed this trend. The flow in the phantom was qualitatively assessed by the velocity profile in the ventricle and by streamlines obtained from 4D phase-contrast MRI.

Conclusion

A multi-modal set of validation data for FSI models has been created, based on parameters relevant for diagnosis of heart valve disease. All data is publicly available for future development of computational heart valve models.
London taxi drivers exploit neighbourhood boundaries for hierarchical route planning
Authors: Griesbauer Eva-Maria , Fernandez Velasco Pablo , Coutrot Antoine , Wiener Jan M. , Morley Jeremy G. , McNamee Daniel , Manley Ed , Spiers Hugo J.
Published: February 2024

Humans show an impressive ability to plan over complex situations and environments. A classic approach to explaining such planning has been tree-search algorithms which search through alternative state sequences for the most efficient path through states. However, this approach fails when the number of states is large due to the time to compute all possible sequences. Hierarchical route planning has been proposed as an alternative, offering a computationally efficient mechanism in which the representation of the environment is segregated into clusters. Current evidence for hierarchical planning comes from experimentally created environments which have clearly defined boundaries and far fewer states than the real-world. To test for real-world hierarchical planning we exploited the capacity of London licensed taxi drivers to use their memory to construct a street by street plan across London, UK (>26,000 streets). The time to recall each successive street name was treated as the response time, with a rapid average of 1.8 seconds between each street. In support of hierarchical planning we find that the clustered structure of London’s regions impacts the response times, with minimal impact of the distance across the street network (as would be predicted by tree-search). We also find that changing direction during the plan (e.g. turning left or right) is associated with delayed response times. Thus, our results provide real-world evidence for how humans structure planning over a very large number of states, and give a measure of human expertise in planning.
Gut feeling: host and habitat as drivers of the microbiome in blackbuck (Antilope cervicapra)
Authors: Jana Ananya , Roy Shamik , Bagchi Sumanta , Isvaran Kavita , Karanth K Praveen
Published: February 2024

The gut microbiome can be shaped by both intrinsic host factors and extrinsic environmental factors. However, the relative importance of intrinsic and extrinsic factors in gut microbial composition has rarely been investigated, particularly for a single host across its natural range. Here, we characterise the gut microbiome of an endemic, endangered antelope, the blackbuck orAntilope cervicapra. We evaluated the influence of seven predictor variables, which were classified into intrinsic and extrinsic factors, on the gut microbiome. We determined which of these seven variables explains greater variation in the microbiome within (α-diversity) and between (β-diversity) the blackbuck host. We analysed the microbiome of 60 blackbuck hosts from ten different populations across India. We recorded 11800 unique OTUs across 30 known phyla and 2.9 million reads. We find an average of 2056 OTUs per individual, with firmicutes and bacteroidetes being the most dominant phyla. We find that nucleotide diversity (intrinsic), blackbuck population density (intrinsic), distance to human settlement (extrinsic), and anthropogenic land-use (extrinsic) explain within-host variation. In contrast, precipitation (extrinsic), nucleotide diversity, distance to human settlement, and anthropogenic land-use explain between-host variation. Overall, we also show that the genetic diversity of the host is more important than their environment for both within- and between-host variation in the microbiome, in blackbuck. Therefore, conservation efforts should be directed to not only preserve natural habitats but also increase the genetic pool of the blackbuck populations, which will positively impact their survival through diverse gut microbiomes.
High or Low Expectations: Expected intensity of action outcome is embedded in action kinetics
Authors: Buaron Batel , Reznik Daniel , Mukamel Roy
Published: February 2024

Goal-directed actions are performed in order to attain certain sensory consequences in the world. However, expected attributes of these consequences can affect the kinetics of the action. In a set of three studies (n=120), we examined how expected attributes of stimulus outcome (intensity) shape the kinetics of the triggering action (applied force), even when the action and attribute are independent. We show that during action execution (button presses), the expected intensity of sensory outcome implicitly affects the applied force of the stimulus-producing action in an inverse fashion. Thus, participants applied more force when the expected intensity of the outcome was low (vs. high intensity outcome). In the absence of expectations or when actions were performed in response to the sensory event, no intensity-dependent force modulations were found. Thus, causality and expectations of stimulus intensity play an important role in shaping action kinetics. Finally, we examined the relationship between kinetics and perception and found no influence of applied force level on perceptual detection of low intensity (near-threshold) outcome stimuli, suggesting no causal link between the two. Taken together, our results demonstrate that action kinetics are implicitly embedded with high-level context such as the expectation of consequence intensity and the causal relationship with environmental cues.
Range ofIxodes laguri, a nidicolous tick that parasitizes critically endangered rodents, with details on its western distribution limit in Austria
Authors: Rubel Franz
Published: February 2024

The nidicolous tickIxodes laguriis a nest-dwelling parasite of small mammals that mainly infest rodents of the families Cricetidae, Gliridae, Muridae and Sciuridae. There is no proven vectorial role forI. laguri, although it is suggested that it is a vector ofFrancisella tularensis. In this study, a first map depicting the entire geographical distribution ofI. laguribased on geo-referenced locations is presented. For this purpose, a digital data set of 141 georeferenced locations from 16 countries was compiled. Particular attention is paid to the description of the westernmost record ofI. laguriin the city of Vienna, Austria. There,I. laguriis specifically associated with its main hosts, the critically endangered European hamster (Cricetus cricetus) and the European ground squirrel (Spermophilus citellus). These two host species have also been mapped in the present paper to estimate the potential distribution ofI. laguriin the Vienna metropolitan region. The range ofI. laguriextends between 16–108° E and 38–54° N, i.e. from Vienna in the east of Austria to Ulaanbaatar, the capital of Mongolia. In contrast to tick species that are expanding their range and are also becoming more abundant as a result of global warming,I. lagurihas become increasingly rare through-out its range. However,I. laguriis not threatened by climate change, but by anthropogenic influences on its hosts and their habitats, which are typically open grasslands and steppes. Rural habitats are threatened by the intensification of agriculture and semi-urban habitats are increasingly being destroyed by urban development.
PiggyBac Transposase Mediated Inducible Trophoblast-specific Knockdown of Mechanistic Target of Rapamycin in Mice Decreases Placental Nutrient Transport and Inhibits Fetal Growth
Authors: Rosario Fredrick J , Urschitz Johann , Razavy Haide , Elston Marlee , Theresa Powell L , Jansson Thomas
Published: February 2024

Abnormal fetal growth is associated with perinatal complications and adult disease. The placental mechanistic target of rapamycin (mTOR) signaling activity is positively correlated to placental nutrient transport and fetal growth. However, if this association represents a mechanistic link, it remains unknown. We hypothesized that trophoblast-specific mTOR knockdown in late pregnant mice decreases placental nutrient transport and inhibits fetal growth. PiggyBac Transposase-Enhanced Pronuclear Injection was performed to generate transgenic mice containing a trophoblast-specific Cyp19I.1 promoter-driven, doxycycline-inducible luciferase reporter transgene with aMtorshRNAmir sequence in its 3’ untranslated region (UTR). We induced mTOR knockdown by administration of doxycycline starting at E14.5. Dams were euthanized at E 17.5, and trophoblast-specific gene targeting was confirmed. Placental mTOR protein expression was reduced by ∼68% in these animals, which was associated with a marked inhibition of mTORC1 and mTORC2 signaling activity. Moreover, we observed a decreased expression of System A amino acid transporter isoform SNAT2 and the System L amino acid transporter isoform LAT1 in isolated trophoblast plasma membranes and lower fetal but not placental weight. Inhibition of trophoblast mTOR signaling in late pregnancy is mechanistically linked to decreased placental nutrient transport and reduced fetal growth. Modulating placental mTOR signaling may represent a novel intervention in pregnancies with abnormal fetal growth.
Random walks with spatial and temporal resets may underlie searching movements in ants
Authors: Lecheval Valentin , Robinson Elva J.H. , Mann Richard P.
Published: February 2024

Abstract

Many ant species are central place foragers, living in a nest and exploiting the surrounding environment. It is however unclear how their exploration behaviour relates to the emerging exploited area. Ants provide a great opportunity to study the emergence of foraging range from individual movements, given the potentially large number of scouting workers involved. Here, we introduce a random walk model with stochastic resetting to depict the movements of searching ants. Stochastic resetting refers to spatially reset at random times the position of agents to a given location, here the nest of searching ants. We investigate the effect of a range of resetting mechanisms by changing how the probability of returning to the nest depends on the duration of unsuccessful foraging trips. We compare the macroscopic predictions of our model to laboratory and field data. We find that the probability for searching ants to return to their nest decreases as the number of foraging trips increases, resulting in scouts going further away from the nest as the number of foraging trips increases. Our findings highlight the importance of resetting random walk models to depict the movements of central place foragers and nurtures novel questions regarding the searching behaviour of ants.
Dose-response functional and transcriptomic effects of follicle-stimulating hormone onex vivomouse folliculogenesis
Authors: Zhan Tingjie , Zhang Jiyang , Zhang Ying , Zhao Qingshi , Chemerinski Anat , Douglas Nataki C. , Zhang Qiang , Xiao Shuo
Published: February 2024

The gonadotropin-dependent phase of ovarian folliculogenesis primarily requires follicle-stimulating hormone (FSH) to support one or multiple antral follicles, dependent on the species, to mature fully, enabling ovarian steroidogenesis, oogenesis, and ovulation to sustain female reproductive cycles and fertility. FSH binds to its membrane receptor in granulosa cells to activate various signal transduction pathways and gene regulatory networks. Poor female reproductive outcomes can result from both FSH insufficiency owing to genetic or non-genetic factors and FSH excess as encountered with ovarian stimulation in assisted reproductive technology (ART), but the underlying molecular mechanisms remain elusive. Herein, we conducted single-follicle and single-oocyte RNA sequencing analysis along with other approaches in anex vivomouse folliculogenesis and oogenesis system to investigate the effects of different concentrations of FSH on key follicular events. Our study revealed that a minimum FSH threshold is required for follicle maturation into the high estradiol-secreting preovulatory stage, and the threshold is moderately variable among individual follicles. FSH at subthreshold, threshold, and suprathreshold levels induced distinct expression patterns of follicle maturation-related genes and the follicular transcriptomics. The RNA-seq analysis identified novel genes and signaling pathways that may critically regulate follicle maturation. Suprathreshold FSH resulted in multiple ovarian disorders including premature luteinization, high production of androgen and proinflammatory factors, and reduced expression of energy metabolism-related genes in oocytes. Together, this study improves our understanding of gonadotropin-dependent folliculogenesis and provides crucial insights into how high doses of FSH used in ART may impact follicular health, oocyte quality, pregnancy outcome, and systemic health.
Urbanization is associated with reduced genetic diversity in marine fish populations
Authors: Karachaliou Eleana , Schmidt Chloé , de Greef Evelien , Docker Margaret F , Garroway Colin J
Published: February 2024

The economic and ecological benefits of living by the ocean have led many coastal settlements to grow into large densely populated cities. Large coastal cities have had considerable environmental effects on marine ecosystems through resource extraction, waste disposal, and use for transportation. Thus, it is important to understand the consequences of urbanization and human activities on evolutionary processes and biodiversity in marine fishes. Using published population genetic datasets for marine fishes amounting to 75,496 individuals sampled from 73 species at 1143 sample sites throughout the world’s oceans, we evaluated how human population density and a composite measure of cumulative human impacts affected genetic diversity and differentiation. We found that genetic diversity was significantly lower in marine fish populations associated with denser human populations regardless of species and locality. The effects of cumulative human impacts on genetic diversity were less prominent, perhaps due to this measure capturing more spatially varying processes. Urbanization in coastal regions has degraded marine biodiversity in a way that erodes adaptive potential for marine fish populations. This highlights the need to mitigate threats from human activities and focus efforts on sustainable urban planning and resource use to conserve marine biodiversity sustaining coastal fisheries and ecosystems.
Temporal dynamics ofCandida albicansmorphogenesis and gene expression reveals distinctions between in vitro and in vivo filamentation
Authors: Wakade Rohan S. , Wellington Melanie , Krysan Damian J.
Published: February 2024

Candida albicansis a common human fungal pathogen that is also a commensal of the oral cavity and gastrointestinal tract.C. albicanspathogenesis is linked to its transition from budding yeast to filamentous morphologies including hyphae and pseudohyphae. The centrality of this virulence trait toC. albicanspathobiology has resulted in extensive characterization a wide range factors associated with filamentation with a strong focus on transcriptional regulation. The vast majority of these experiments have used in vitro conditions to induce the yeast-to-filament transition. Taking advantage of in vivo approaches to quantitatively characterize both morphology and gene expression during filamentation during mammalian infection, we have investigated the dynamics of these two aspects of filamentation in vivo and compared them to in vitro filament induction with “host-like” tissue culture media supplemented with serum at mammalian body temperature. Although filamentation shares many common features in the two conditions, we have found two significant differences. First, alternative carbon metabolism genes are expressed early during in vitro filamentation and late in vivo, suggesting significant differences in glucose availability. Second,C. albicansbegins a hyphae-to-yeast transition after 4hr incubation while we find little evidence of hyphae-to-yeast transition in vivo up to 24hr post infection. We show that the low rate of in vivo hyphae-to-yeast transition is likely due to very low expression ofPES1, a key driver of lateral yeast in vitro, and that heterologous expression ofPES1is sufficient to trigger lateral yeast formation in vivo.

Importance

Candida albicansfilamentation is correlated with virulence and is an intensively studied aspect ofC. albicans biology. The vast majority of studies onC. albicansfilamentation are based on in vitro induction of hyphae and pseudohyphae. Here we used an in vivo filamentation assay and in vivo expression profiling to compare the tempo of morphogenesis and gene expression between in vitro and in vivo filamentation. Although the hyphal gene expression profile is induced rapidly in both conditions, it remains stably expressed over a 12hr time course in vivo while it peaks after 4hr in vitro and is reduced. This reduced hyphal gene expression in vitro correlates with reduced hyphae and increased hyphae-to-yeast transition. In contrast, there is little evidence of evidence of hyphae-to-yeast transition in vivo.
Lung-resident memory B cells maintain allergic IgE responses in the respiratory tract
Authors: Nelson Alexander J. , Tatematsu Bruna K. , Beach Jordan R. , Sojka Dorothy K. , Wu Yee Ling
Published: February 2024

Allergen-specific IgE is a key mediator of allergic asthma. However, the tissue sites and cell types that support IgE production at the mucosa remained undefined. Here, we reveal that inhaled allergens induce the formation of IgG1+lung-resident memory B cells (MBC) that switch to IgE. Using a mouse reporter for IgE class switch recombination, a requirement for the generation of IgE, we identify lung tissues as a major site of IgE class switching, which is dominated by IgG1+MBCs and supported by IL-4-producing TH2 cells. This is in sharp contrast to what occurs in the draining lymph nodes where germinal center B cells are the IgE-switching population and TFHcells provide IL-4. By single-cell transcriptomic analyses, we reveal potential mechanisms for the formation of lung-resident MBCs. Altogether, this study identifies the origin of allergen-specific IgE in the respiratory tract and explains how local chronic hypersensitivity is maintained in allergic asthma.
Chromatin regulatorKdm6bis required for the establishment and maintenance of neural stem cells in mouse hippocampus
Authors: Gil Eugene , Hong Sung Jun , Wu David , Park Dae Hwi , Delgado Ryan N. , Malatesta Martina , Ahanger Sajad Hamid , Lin Karin , Villeda Saul , Lim Daniel A.
Published: February 2024

Neural stem cells (NSCs) in the mouse hippocampal dentate gyrus (DG) – a structure important to learning and memory – generate new neurons postnatally and throughout adult life. However, the regulators that enable this lifelong neurogenesis remain incompletely understood. Here we show that the chromatin regulator KDM6B is required for both the establishment and maintenance of NSCs in the mouse DG. Conditional deletion ofKdm6bin embryonic DG precursors results in an adult hippocampus that is essentially devoid of NSCs, and hippocampal-dependent behaviors are defective.Kdm6b-deletion causes precocious neuronal differentiation, and the NSC population fails to become established in the postnatal DG. Using single cell RNA sequencing (scRNA-seq), we observed thatKdm6b-deletion disrupts the transcriptomic signature of NSC maintenance. Furthermore, deletingKdm6bin adult DG NSCs induces early neuronal differentiation, and the NSC population is not properly maintained. These data illustrate the critical role thatKdm6bplays in adult DG neurogenesis, which may help understand how mutations in this chromatin regulator result in cognitive disorders in human patients.
TFEB controls syncytiotrophoblast differentiation
Authors: Esbin Meagan N. , Dahal Liza , Fan Vinson B. , McKenna Joey , Yin Eric , Darzacq Xavier , Tjian Robert
Published: February 2024

During human development, a subset of differentiating fetal cells form a temporary organ, the placenta, which invades the uterine wall to support nutrient, oxygen, and waste exchange between the mother and fetus until birth. Most of the human placenta is formed by a syncytial villous structure which arises via cell-cell fusion of underlying fetal trophoblast stem cells. Genetic and functional studies have characterized the membrane protein fusogens, Syncytin-1 and Syncytin-2, that are both necessary and sufficient for human trophoblast cell-cell fusion. However, identification and characterization of upstream transcriptional regulators regulating their expression has been limited. Here, using CRISPR knockout in anin vitrocellular model of syncytiotrophoblast development (BeWo cells), we find that the transcription factor TFEB, mainly known as a regulator of autophagy and lysosomal biogenesis, is required for cell-cell fusion of syncytiotrophoblasts. TFEB translocates to the nucleus, exhibits increased chromatin interactions, and directly binds the Syncytin-1 and Syncytin-2 promoters to control their expression during differentiation. While TFEB appears to play an important role in syncytiotrophoblast differentiation, ablation of TFEB largely does not affect lysosomal gene expression or lysosomal biogenesis in differentiating BeWo cells, suggesting that TFEB plays an alternative role in placental cells.
2-D Neural Geometry Underpins Hierarchical Organization of Sequence in Human Working Memory
Authors: Fan Ying , Wang Muzhi , Ding Nai , Luo Huan
Published: February 2024

Working memory (WM) is constructive in nature. Instead of passively retaining information, WM reorganizes complex sequences into hierarchically embedded chunks to overcome capacity limits and facilitate flexible behavior. To investigate the neural mechanisms underlying hierarchical reorganization in WM, we performed two electroencephalography (EEG) and one magnetoencephalography (MEG) experiments, wherein humans retain in WM a temporal sequence of items, i.e., syllables, which are organized into chunks, i.e., multisyllabic words. We demonstrate that the 1-D sequence is represented by 2-D neural representational geometry in WM arising from parietal-frontal regions, with separate dimensions encoding item position within a chunk and chunk position in the sequence. Critically, this 2-D geometry is observed consistently in different experimental settings, even during tasks discouraging hierarchical reorganization in WM and correlates with WM behavior. Overall, these findings strongly support that complex sequences are reorganized into factorized multi-dimensional neural representational geometry in WM, which also speaks to general structure-based organizational principles given WM’s involvement in many cognitive functions.
Accurate Bayesian phylogenetic point estimation using a tree distribution parameterized by clade probabilities
Authors: Berling Lars , Klawitter Jonathan , Bouckaert Remco , Xie Dong , Gavryushkin Alex , Drummond Alexei J.
Published: February 2024

Bayesian phylogenetic analysis with MCMC algorithms generates an estimate of the posterior distribution of phylogenetic trees in the form of a sample of phylogenetic trees and related parameters. The high dimensionality and non-Euclidean nature of tree space complicates summarizing the central tendency and variance of the posterior distribution in tree space. Here we introduce a new tractable tree distribution and associated point estimator that can be constructed from a posterior sample of trees. Through simulation studies we show that this point estimator performs at least as well and often better than standard methods of producing Bayesian posterior summary trees. We also show that the method of summary that performs best depends on the sample size and dimensionality of the problem in non-trivial ways.

Author summary

Our research introduces novel methods to analyse a set of phylogenetic tree topologies, such as those generated by Bayesian Markov Chain Monte Carlo algorithms. We define a new model for a distribution on trees that is based on observed clade frequencies. We study it together with closely related models that are based on observed clade split frequencies. These distributions are easy to work with and, as we show experimentally, provide excellent estimates of the true posterior distribution. Furthermore, we demonstrate that they enable us to find the tree with the highest posterior probability, which acts as a summary tree or point estimate of the distribution. In simulation studies, we show that the new methods performs as least as well or better than existing methods. Additionally, we highlight that choosing the best method for summarizing sets of trees remains challenging, as it depends on the sample size and complexity of the problem in non-trivial ways. This work has the potential to improve the accuracy of phylogenetic studies.
PreMode predicts mode-of-action of missense variants by deep graph representation learning of protein sequence and structural context
Authors: Zhong Guojie , Zhao Yige , Zhuang Demi , Chung Wendy K , Shen Yufeng
Published: February 2024

Accurate prediction of the functional impact of missense variants is important for disease gene discovery, clinical genetic diagnostics, therapeutic strategies, and protein engineering. Previous efforts have focused on predicting a binary pathogenicity classification, but the functional impact of missense variants is multi-dimensional. Pathogenic missense variants in the same gene may act through different modes of action (i.e., gain/loss-of-function) by affecting different aspects of protein function. They may result in distinct clinical conditions that require different treatments. We developed a new method, PreMode, to perform gene-specific mode-of-action predictions. PreMode models effects of coding sequence variants using SE(3)-equivariant graph neural networks on protein sequences and structures. Using the largest-to-date set of missense variants with known modes of action, we showed that PreMode reached state-of-the-art performance in multiple types of mode-of-action predictions by efficient transfer-learning. Additionally, PreMode’s prediction of G/LoF variants in a kinase is consistent with inactive-active conformation transition energy changes. Finally, we show that PreMode enables efficient study design of deep mutational scans and optimization in protein engineering.
Correlation between bioluminescent blinks and swimming behavior in the splitfin flashlight fishAnomalops katoptron
Authors: Jägers Peter , Frischmuth Timo , Herlitze Stefan
Published: February 2024

The light organs of the splitfin flashlight fishAnomalops katoptronare necessary for schooling behavior, to determine nearest neighbor distance, and to feed on zooplankton under dim light conditions. Each behavior is coupled to context-dependent blink frequencies and can be regulated via mechanical occlusion of light organs. During shoaling in the laboratory individuals show moderate blink frequencies around 100 blinks per minute. In this study, we correlated bioluminescent blinks with the spatio-temporal dynamics of swimming profiles in three dimensions, using a stereoscopic, infrared camera system. Groups of flashlight fish showed intermediate levels of polarization and distances to the group centroid. Individuals showed higher swimming speeds and curved swimming profiles during light organ occlusion. The largest changes in swimming direction occurred when darkening the light organs. BeforeA. katoptronexposed light organs again, they adapted a nearly straight movement direction. Light organs create a strong contrast against the background. Therefore, a close combination of light signals and movement is crucial to the behavior ofA. katoptron.