bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of proximity to criticality enhances slow activity fluctuations during free recall
Authors: Yellin D. , Siegel N. , Malach R. , Shriki O.
Published: February 2023

Categorically bounded free recall allows generating perceptual and cognitive contents within specific categories while avoiding unrelated intrusions. Previous research suggested that this is implemented via amplification of ultra-slow spontaneous activity fluctuations, initiating a spontaneous recall event. However, the underlying amplification mechanism remains unclear. Here, we demonstrate, using a simulation of a simple random recurrent neuronal network operating near a critical point, that such selective amplification can be generated by a small shift towards this critical point, resulting in a dynamical phenomenon termed “critical slowing down”. By fitting physiological parameters and applying stochastic white noise input, we simulated ultra-slow fluctuations observed during rest and categorically bounded visual recall in the human cortex. Our findings suggest that modulation of spontaneous fluctuations linked to free recall can be explained by a stochastically driven recurrent network near a critical point, providing insight into the rapid and flexible formation of categorical boundaries in human cognition.
Crop microbiome responses to pathogen colonisation regulate the host plant defence
Authors: Liu Hongwei , Wang Juntao , Delgado-Baquerizo Manuel , Zhang Haiyang , Li Jiayu , Singh Brajesh
Published: February 2023

Aims

Soil-borne pathogens severely damage the yield and quality of crops worldwide. Plant and soil microbiomes (e.g. in the rhizosphere) intimately interact with the plant, the pathogen and influence outcomes of disease infection. Investigation of how these microbiomes respond to disease infection is critical to develop solutions to control diseases.

Methods

Here, we conducted a field experiment and collected healthy and crown rot disease infected (caused byFusarium pseudograminearum,Fp) wheat plants. We investigated their microbiomes in different compartments, plant immune responses and interactions with the pathogen (Fp) aiming at advancing our knowledge on microbiome-mediated regulation of plant responses to pathogens.

Results

We found thatFpcolonised wheat plants in significant loads, accounting for 11.3% and 60.7% of the fungal communities in the rhizosphere and root endosphere, respectively. However,Fppresented with a small fraction of the leaf microbiome, up to 1.2%. Furthermore,Fp-infection led to significant changes in the composition of the microbial communities in the rhizosphere and root endosphere while had little impact on leaves. We further found that wheat defence signalling pathways, wheat microbiomes and the pathogen intimately correlated with each other in structural equation modelling. As such, we also identified ecological clusters explained changes in the wheat defence signalling pathways. Lastly, microbial co-occurrence network complexity was higher inFp-infected plants relative to healthy plants, suggesting thatFp-infection has potentially induced more microbial interactions in plants.

Conclusions

We provide novel evidence that soil-borne diseases significantly disrupt belowground plant microbiomes influencing the responses of plant immunity to pathogens.
Volume loss and recovery in bovine knee meniscus loaded in circumferential tension
Authors: Peloquin John M. , Santare Michael H. , Elliott Dawn M.
Published: February 2023

Load-induced volume change is an important aspect of knee meniscus function because volume loss creates fluid pressure, which minimizes friction and helps support compressive loads. The knee meniscus is unusual amongst cartilaginous tissues in that it is loaded not only in axial compression, but also in circumferential tension between its tibial attachments. Despite the physiologic importance of the knee meniscus’ tensile properties, its volumetric strain in tension has never been directly measured, and predictions of volume strain in the scientific literature are inconsistent. In this study, we apply uniaxial tension to bovine knee meniscus and use biplanar imaging to directly observe the resulting 3D volume change and unloaded recovery, revealing that tension causes volumetric contraction. Compression is already known to also cause contraction; therefore, all major physiologic loads compress and pressurize the meniscus, inducing fluid outflow. Although passive unloaded recovery is often described as slow relative to loaded loss, here we show that at physiologic strains the volume recovery rate in the meniscus upon unloading is faster than the rate of volume loss. These measurements of volumetric strain are an important step towards a complete theory of knee meniscus fluid flow and load support.
Architectural experience influences the processing of others’ body expressions
Authors: Presti Paolo , Galasso Gaia Maria , Ruzzon Davide , Avanzini Pietro , Caruana Fausto , Rizzolatti Giacomo , Vecchiato Giovanni
Published: February 2023

The interplay between space and cognition is a crucial issue in Neuroscience leading to the development of multiple research fields. However, the relationship between architectural space, the movement of the inhabitants and their interactions has been too often neglected, failing to provide a unifying view of architecture’s capacity to modulate social cognition broadly.

We bridge this gap by requesting participants to judge avatars’ emotional expression (high vs. low arousal) at the end of their promenade inside high- or low-arousing architectures. Stimuli were presented in virtual reality to ensure a dynamic, naturalistic experience. High-density EEG was recorded to assess the neural responses to the avatar’s presentation.

Observing highly aroused avatars increased Late Positive Potentials (LPP), in line with previous evidence. Strikingly, 250 ms before the occurrence of the LPP, P200 amplitude increased due to the experience of low-arousing architectures paralleling increased subjective arousal reports and fixation times on the avatar’s head. Source localization highlighted a contribution of the right dorsal premotor cortex to both P200 and LPP.

In conclusion, the immersive and dynamic architectural experience modulates human social cognition. In addition, the motor system plays a role in processing architecture and body expressions proving how the space and social cognition interplay is rooted in common neural substrates. This study demonstrates that the manipulation of mere architectural space is sufficient to influence human behavior in social interactions.

Significance Statement

In the last thirty years the motor system has been recognized as a fundamental neural machinery for spatial and social cognition, making worthwhile the investigation of the interplay between architecture and social behavior. Here, we show that the motor system participates in the others’ body expression processing in two stages: the earliest influenced by the dynamic architectural experience, the latter modulated by the actual physical characteristics. These findings highlight the existence of motor neural substrates common to spatial and social cognition, with the architectural space exerting an early and possibly adapting effect on the later social experience. Since mere architectural forms influence human behavior, a proper spatial design could thus facilitate everyday social interactions.
Coexistence in Periodic Environments
Authors: Scott Alexa M , Bieg Carling , McMeans Bailey C , McCann Kevin S
Published: February 2023

Climate change and other anthropogenic impacts are rapidly altering natural environmental periodicities on a variety of time scales. Despite this, a general theoretical foundation describing the role of periodic environmental variation in structuring species interactions and ecological communities is still underdeveloped. Alarmingly, this leaves us unprepared to understand and predict implications for the maintenance of biodiversity under global change. Here, we extend a two-species Lotka-Volterra competition model that incorporates periodic forcing between seasons of high and low production to investigate the effects of changing environmental patterns on species coexistence. Towards this, we define coexistence criteria for periodic environments by approximating isocline solutions akin to classical coexistence outcomes. This analytical approach illustrates that periodic environments (i.e., seasonality) in and of themselves can mediate different competitive outcomes, and these patterns are general across varying time scales. Importantly, species coexistence may be incredibly sensitive to changes in these abiotic periods, suggesting that climate change has the potential to drastically impact the maintenance of biodiversity in the future.
Why Do Hybrids Turn Down Sex?
Authors: Fyon Frederic , Berbel-Filho Waldir Miron , Schlupp Ingo , Wild Geoff , Ubeda Francisco
Published: February 2023

Asexual reproduction is ancestral in prokaryotes; the switch to sexuality in eukaryotes is one of the major transitions in the history of life. The study of the maintenance of sex in eukaryotes has raised considerable interest for decades and is still one of evolutionary biology’s most prominent question. The observation that many asexual species are of hybrid origin have led some to propose that asexuality in hybrids results from sexual processes being disturbed because of incompatibilities between the two parental species’ genomes. This proximate theory appears difficult in real life, as it requires fundamental reproductive traits to be profoundly altered without collapsing individuals’ fertility. Repeated failures to produce asexual Amazon Molly in the lab through crossing experiments show that we are still in need of an evolutionary explanation. Here, we present a mathematical model and propose an adaptive route for the evolution of asexuality from previously sexual hybrids. Under smaller reproductive alterations, we show that asexuality can evolve to rescue hybrids’ reproduction. Importantly, we highlight that when incompatibilities only affect the fusion of sperm and egg’s genomes, unreduced meiosis and paternal genome elimination can evolve separately, greatly facilitating the overall evolutionary route.
Characterization of new highly selective pyrazolo[4,3-d]pyrimidine inhibitor of CDK7
Authors: Kovalová Markéta , Havlíček Libor , Djukic Stefan , Škerlová Jana , Peřina Miroslav , Pospíšil Tomáš , Řezníčková Eva , Řezáčová Pavlína , Jorda Radek , Kryštof Vladimír
Published: February 2023

Targeting cyclin-dependent kinase 7 (CDK7) provides an interesting therapeutic option in cancer therapy because this kinase participates in regulating the cell cycle and transcription. Here, we describe a new trisubstituted pyrazolo[4,3-d]pyrimidine derivative, LGR6768, that inhibits CDK7 in the nanomolar range and displays favourable selectivity across the CDK family. We determined the structure of fully active CDK2/cyclin A2 in complex with LGR6768 at 2.6 Å resolution using X-ray crystallography, revealing conserved interactions within the active site. Structural analysis and comparison with LGR6768 docked to CDK7 provides an explanation of the observed biochemical selectivity, which is linked to a conformational difference in the biphenyl moiety. In cellular experiments, LGR6768 affected regulation of the cell cycle and transcription by inhibiting the phosphorylation of cell cycle CDKs and the carboxy-terminal domain of RNA polymerase II, respectively. LGR6768 limited the proliferation of several leukaemia cell lines, triggered significant changes in protein and mRNA levels related to CDK7 inhibition and induced apoptosis in dose- and time-dependent experiments. Our work supports previous findings and provides further information for the development of selective CDK7 inhibitors.

Graphical abstract
Diet influences resource allocation in chemical defence but not melanin synthesis in an aposematic moth
Authors: Ottocento Cristina , Rojas Bibiana , Burdfield-Steel Emily , Furlanetto Miriam , Nokelainen Ossi , Winters Sandra , Mappes Johanna
Published: February 2023

For animals that synthesise their chemical compoundsde novo, resources, particularly proteins, can influence investment in chemical defences and nitrogen-based wing colouration such as melanin. Competing for the same resources often leads to trade-offs in resource allocation. We manipulated protein availability in the larval diet of the wood tiger moth,Arctia plantaginis, to test how early life resource availability influences relevant life history traits, melanin production, and chemical defences. We expected higher dietary protein to result in more effective chemical defences and a higher amount of melanin in the wings. According to the resource allocation hypothesis, we also expected individuals with less melanin to have more resources to allocate to chemical defences. We found that protein-deprived moths had a slower larval development, and their chemical defences were less unpalatable for bird predators, but the expression of melanin in their wings did not differ from that of moths raised on a high-protein diet. The amount of melanin in the wings, however, unexpectedly correlated positively with chemical defences, irrespective of the diet they were raised on. Our findings demonstrate that the resources available in early life have an important role in the efficacy of chemical defences, but melanin-based warning colours are less sensitive to resource variability than other fitness-related traits.
Synergistic survival-related effects of larval exposure to an aquatic pollutant and food stress get stronger during and especially after metamorphosis and shape fitness of terrestrial adults
Authors: Jorissen Sarah , Janssens Lizanne , Verheyen Julie , Stoks Robby
Published: February 2023

To improve the ecological risk assessment of aquatic pollutants it is needed to study their effects not only in the aquatic larval stage, but also in the terrestrial adult stage of the many animals with a complex life cycle. This remains understudied, especially with regard to interactive effects between aquatic pollutants and natural abiotic stressors. We studied effects of exposure to the pesticide DNP (2,4-Dinitrophenol) and how these were modulated by limited food availability in the aquatic larvae, and the possible delayed effects in the terrestrial adults of the damselflyLestes viridis. Our results revealed that DNP and low food each had large negative effects on the life history, behaviour and to a lesser extent on the physiology of not only the larvae, but also the adults. Food limitation magnified the negative effects of DNP as seen by a strong decline in larval survival, metamorphosis success and adult lifespan. Notably, the synergism between the aquatic pollutant and food limitation for survival-related traits was stronger in the non-exposed adults than in the exposed larvae, likely because metamorphosis is stressful itself. Our results highlight that identifying effects of aquatic pollutants and synergisms with natural abiotic stressors, not only in the aquatic larval but also in the terrestrial adult stage, is crucial to fully assess the ecological impact of aquatic pollutants and to reveal the impact on the receiving terrestrial ecosystem through a changed aquatic-terrestrial subsidy.
Benchmarking differential abundance methods for finding condition-specific prototypical cells in multi-sample single-cell datasets
Authors: Yi Haidong , Plotkin Alec , Stanley Natalie
Published: February 2023

Modern single-cell data analysis relies on statistical testing (e.g. differential expression testing) to identify genes or proteins that are up-or down-regulated in relation to cell-types or clinical outcomes. However, existing algorithms for such statistical testing are often limited by technical noise and cellular heterogeneity, which lead to false-positive results. To constrain the analysis to a compact and phenotype-related cell population, differential abundance (DA) testing methods were employed to identify subgroups of cells whose abundance changed significantly in response to disease progression, or experimental perturbation. Despite the effectiveness of DA testing algorithms of identifying critical cell-states, there are no systematic benchmarking or comparative studies to compare their usages in practice. Herein, we performed the first comprehensive benchmarking study to objectively evaluate and compare the benefits and potential downsides of current state-of-the-art DA testing methods. We benchmarked six DA testing methods on several practical tasks, using both synthetic and real single-cell datasets. The task evaluated include, recognizing true DA subpopulations, appropriate handing of batch effects, runtime efficiency, and hyperparameter usability and robustness. Based on various evaluation results, this paper gives dataset-specific suggestions for the usage of DA testing methods.
Influence of Demographic, Socio-economic, and Brain Structural Factors on Adolescent Neurocognition: A Correlation Analysis in the ABCD Initiative
Authors: Hussain Mohammad Arafat , Li Grace , Grant Ellen , Ou Yangming
Published: February 2023

The Adolescent Brain Cognitive Development (ABCD) initiative is a longitudinal study aimed at characterizing brain development from childhood through adolescence and identifying key biological and environmental factors that influence this development. The study measures neurocognitive abilities across a multidimensional array of functions, with a focus on the critical period of adolescence during which physical and socio-emotional changes occur and the structure of the cortical and white matter changes. In this study, we perform a correlation analysis to examine the linear relation of adolescent neurocognition functions with the demographic, socio-economic, and magnetic resonance imaging-based brain structural factors. The overall goal is to obtain a comprehensive understanding of how natural and nurtural factors influence adolescent neurocognition. Our results on>10,000 adolescents show many positive and negative statistical significance interrelations of different neurocognitive functions with the demographic, socioeconomic, and brain structural factors, and also open up questions inviting further future studies.
Brain Structure and Working Memory Adaptations Associated with Maturation and Aging in Mice
Authors: Clifford Kevan P. , Miles Amy E. , Prevot Thomas D. , Misquitta Keith A. , Ellegood Jacob , Lerch Jason P. , Sibille Etienne , Nikolova Yuliya S. , Banasr Mounira
Published: February 2023

Introduction

As the population skews toward older age, elucidating mechanisms underlying human brain aging becomes imperative. Structural MRI has facilitated non-invasive investigation of lifespan brain morphology changes, yet this domain remains uncharacterized in rodents despite increasing use as models of disordered human brain aging.

Methods

Young (2m, n=10), middle-age (10m, n=10) and old (22m, n=9) mice were utilized for maturational (young vs. middle-age) and aging-related (middle-age vs. old mice) comparisons. Regional brain volume was averaged across hemispheres and reduced to 32 brain regions. Pairwise group differences in regional volume, residualized for total brain volume, and associations between volume and cognitive performance on the Y-maze task were tested. General linear models with total brain volume as a covariate, and logistic regression for sample wide associations were employed respectively, correcting for multiple comparisons. Structural covariance networks were generated using the R package ‘igraph’. Group differences in network centrality (degree), integration (mean distance), and segregation (transitivity, modularity) were tested across network densities (5–40%), using 5,000 (1,000 for degree) permutations with significance criteria of p<0.05 at ≥5 consecutive density thresholds.

Results

Widespread significant maturational changes in volume occurred in 18 brain regions, including considerable loss in isocortex regions and increases in brainstem regions and white matter tracts. The aging-related comparison yielded 6 significant changes in brain volume, including further loss in isocortex regions and increases in white matter tracts. No significant volume changes were observed across either comparison for subcortical regions. Additionally, smaller volume of the anterior cingulate area (χ2=2.325, pbh=0.044) and larger volume of the hippocampal formation (χ2=-2.180, pbh=0.044) were associated with poorer cognitive performance. Maturational network comparisons yielded significant degree changes in 9 regions, but no aging related changes, aligning with network stabilization trends in humans. Maturational decline in modularity occurred (24-29% density), mirroring human trends of decreased segregation in young adulthood, while mean distance and transitivity remained stable.

Conclusions/Implications

These findings offer a foundational account of age effects on brain volume, structural brain networks, and cognition in mice, informing future work in facilitating translation between rodent models and human brain aging.
Strategies for effectively modelling promoter-driven gene expression using transfer learning
Authors: Reddy Aniketh Janardhan , Herschl Michael H. , Geng Xinyang , Kolli Sathvik , Lu Amy X. , Kumar Aviral , Hsu Patrick D. , Levine Sergey , Ioannidis Nilah M.
Published: February 2023

The ability to deliver genetic cargo to human cells is enabling rapid progress in molecular medicine, but designing this cargo for precise expression in specific cell types is a major challenge. Expression is driven by regulatory DNA sequences within short synthetic promoters, but relatively few of these promoters are cell-type-specific. The ability to design cell-type-specific promoters using model-based optimization would be impactful for research and therapeutic applications. However, models of expression from short synthetic promoters (promoter-driven expression) are lacking for most cell types due to insufficient training data in those cell types. Although there are many large datasets of both endogenous expression and promoter-driven expression in other cell types, which provide information that could be used for transfer learning, transfer strategies remain largely unexplored for predicting promoter-driven expression. Here, we propose a variety of pretraining tasks, transfer strategies, and model architectures for modelling promoter-driven expression. To thoroughly evaluate various methods, we propose two benchmarks that reflect data-constrained and large dataset settings. In the data-constrained setting, we find that pretraining followed by transfer learning is highly effective, improving performance by 24 − 27%. In the large dataset setting, transfer learning leads to more modest gains, improving performance by up to 2%. We also propose the best architecture to model promoter-driven expression when training from scratch. The methods we identify are broadly applicable for modelling promoter-driven expression in understudied cell types, and our findings will guide the choice of models that are best suited to designing promoters for gene delivery applications using model-based optimization. Our code and data are available athttps://github.com/anikethjr/promoter_models.
Effects of pasteurization on osteopontin levels in human breastmilk and pasteurized breastmilk products
Authors: McClanahan Kathleen G. , Reese Jeff , Weitkamp Jörn-Hendrik , Olivares-Villagómez Danyvid
Published: February 2023

Background

Osteopontin (OPN) is an important breastmilk protein involved in infant intestinal, immunological, and brain development. However, little is known about how common milk pasteurization and storage techniques affect this important bioactive protein.

Methods

Human milk osteopontin concentration was measured in single-donor fresh or frozen breastmilk, pooled Holder-pasteurized donor breastmilk, and a shelf-stable (retort pasteurized) breastmilk product by ELISA. Breastmilk samples were pasteurized and/or frozen before measuring osteopontin concentrations.

Results

Holder pasteurization of breastmilk resulted in an ∼50% decrease in osteopontin levels within single-donor samples, whereas pooled donor breastmilk had comparable osteopontin levels to non-pasteurized single-donor samples. Breastmilk from mothers of preterm infants trended toward higher osteopontin concentration than mothers of term infants; however, samples from preterm mothers experienced greater osteopontin degradation upon pasteurization. Finally, freezing breastmilk prior to Holder pasteurization resulted in less osteopontin degradation than Holder pasteurization prior to freezing.

Conclusion

Commonly used breastmilk pasteurization and storage techniques, including freezing, Holder and retort pasteurization, decrease the levels of the bioactive protein osteopontin in human breastmilk.

Impact

Pasteurization of human breastmilk significantly decreases the levels of the bioactive protein osteopontin

Use of both pasteurization and freezing techniques for breastmilk preservation results in greater loss of osteopontin

This study presents for the first time an analysis of osteopontin levels in single-donor pasteurized milk samples
Dynamical modeling reveals RNA decay mediates the effect of matrix stiffness on aged muscle stem cell fate
Authors: Hettinger Zachary R. , Hu Sophia , Mamiya Hikaru , Sahu Amrita , Iijima Hirotaka , Wang Kai , Gilmer Gabrielle , Miller Amanda , Nasello Gabriele , D’Amore Antonio , Vorp David A. , Rando Thomas A. , Xing Jianhua , Ambrosio Fabrisia
Published: February 2023

Loss of muscle stem cell (MuSC) self-renewal with aging reflects a combination of influences from the intracellular (e.g., post-transcriptional modifications) and extracellular (e.g., matrix stiffness) environment. Whereas conventional single cell analyses have revealed valuable insights into factors contributing to impaired self-renewal with age, most are limited by static measurements that fail to capture nonlinear dynamics. Using bioengineered matrices mimicking the stiffness of young and old muscle, we showed that while young MuSCs were unaffected by aged matrices, old MuSCs were phenotypically rejuvenated by young matrices. Dynamical modeling of RNA velocity vector fieldsin silicorevealed that soft matrices promoted a self-renewing state in old MuSCs by attenuating RNA decay. Vector field perturbations demonstrated that the effects of matrix stiffness on MuSC self-renewal could be circumvented by fine-tuning the expression of the RNA decay machinery. These results demonstrate that post-transcriptional dynamics dictate the negative effect of aged matrices on MuSC self-renewal.

Graphical Abstract

Graphical abstract description:

The balance of self-renewal and differentiation in young muscle stem cells (MuSCs) is robust to perturbations of the biophysical microenvironment. In contrast, aged MuSCs are highly sensitive to extrinsic perturbations, and exposure to a youthful microenvironment rejuvenates the self-renewing potential of aged MuSCs by modulating post-transcriptional RNA dynamics.
The cardiac myosin binding protein-C phosphorylation state as a function of multiple protein kinase and phosphatase activities
Authors: Kampourakis Thomas , Ponnam Saraswathi , Koch Daniel
Published: February 2023

Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) is a crucial determinant of cardiac myofilament function. Although cMyBP-C phosphorylation by various protein kinases has been extensively studied, the influence of protein phosphatases on cMyBP-C’s multiple phosphorylation sites has remained largely obscure. Here we provide a detailed biochemical characterization of cMyBP-C dephosphorylation by protein phosphatases 1 and 2A (PP1 and PP2A) and develop an integrated kinetic model for cMyBP-C phosphorylation using data for both PP1, PP2A and protein kinases A (PKA), C and RSK2. We find strong site-specificity and a hierarchical mechanism for both phosphatases, proceeding in the opposite direction of sequential phosphorylation by PKA. The model is consistent with published data from human patients and predicts complex non-linear cMyBP-C phosphorylation patterns that are validated experimentally. Our results emphasize the importance of phosphatases for cMyBP-C regulation and prompt us to propose reciprocal relationships between cMyBP-C m-motif conformation, phosphorylation state and myofilament function.
Carbonate bedrock may not alleviate DIC limitation of snow algae — a test of hypothesis in the Medicine Bow Mountains, WY, USA
Authors: Hamilton Trinity L. , Havig Jeff
Published: February 2023

Snow is a critical component of the Earth system. High elevation snow can persist into the melt season and hosts a diverse array of life including snow algae. Due in part to the presence of pigments, snow algae lower albedo and accelerate snow melt which has led to increasing interest in identifying and quantifying the environmental factors that constrain their distribution. Dissolved inorganic carbon (DIC) concentration is low in supraglacial snow on Cascade stratovolcanoes and snow algae primary productivity can be stimulated through DIC addition. Here we asked if CO2would still be a limiting nutrient for snow hosted on glacially eroded carbonate bedrock (which could provide an additional source of DIC). We assayed snow algae communities for nutrient and DIC limitation on two seasonal snowfields on glacially eroded carbonate bedrock in the Snowy Range of the Medicine Bow Mountains, Wyoming, USA. DIC stimulated snow algae primary productivity in snow with lower DIC concentration despite the presence of carbonate bedrock, which alleviated DIC limitation in the other site. Our results support the hypothesis that increased atmospheric CO2concentrations may lead to larger and more robust snow algae blooms globally, even for sites with carbonate bedrock.
Go thou to the ant: A comparative biomechanical analysis of locomotion in Hymenoptera (Hexapoda)
Authors: Regeler V. , Boudinot B.E. , Wöhrl T.
Published: February 2023

Although ants are conceived of as paragons of social complexity, it may be their locomotory capacity that truly sets them apart from other Hymenoptera. Based on our comparative kinematic analysis of Formicidae for level, straight-line locomotion in a broad phylogenetic context, we observe that ants are distinctly capable runners. No sampled hymenopteran paralleled the body-scaled speed of ants. Relative stride lengths for ants were longer than other sampled taxa despite short ground contact durations relative to swing durations. With respect to spatial gait patterns, ants had relatively narrow hindleg and broad midleg step-widths on average, possibly enhancing speed and turning ability. Ants were able to extend their propulsive pair of legs, those of the metathorax, extremely far posterad relative to other sampled taxa, and had a distinct locomotory posture, with a high ground clearance and the femorotibial joints raised above their backs. Despite the unique modifications of their coxotrochanteral articulations, ant forelimbs were largely unremarkable with respect to our quantified variables. Sawflies, in contrast, had extremely wide and perhaps inefficient foreleg stances, and were observed for the first time to have what appears to be a dominant tetrapodal gait pattern, which raises unexpected questions about the early evolution of the Hymenoptera. Finally, we observed variability in attachment abilities and no consistent pattern of leg liftoff sequence across the sampled taxa. Our results establish locomotory evolution in the Hymenoptera as a functionally and structurally variable system with numerous directions of future research, particularly for phylogenetic comparison across wing-monomorphic and wing-polymorphic lineages.

Summary statement

This work establishes a comparative phylogenetic approach to hymenopteran kinematics, demonstrating that ant locomotory capacity is derived and observes, unexpectedly, that the sampled sawflies (symphyta) never used a tripod gait.
PIFiA: Self-supervised Approach for Protein Functional Annotation from Single-Cell Imaging Data
Authors: Razdaibiedina Anastasia , Brechalov Alexander , Friesen Helena , Usaj Mojca Mattiazzi , Masinas Myra Paz David , Suresh Harsha Garadi , Wang Kyle , Boone Charles , Ba Jimmy , Andrews Brenda
Published: February 2023

Fluorescence microscopy data describe protein localization patterns at single-cell resolution and have the potential to reveal whole-proteome functional information with remarkable precision. Yet, extracting biologically meaningful representations from cell micrographs remains a major challenge. Existing approaches often fail to learn robust and noise-invariant features or rely on supervised labels for accurate annotations. We developed PIFiA, (ProteinImage-basedFunctionalAnnotation), a self-supervised approach for protein functional annotation from single-cell imaging data. We imaged the global yeast ORF-GFP collection and applied PIFiA to generate protein feature profiles from single-cell images of fluorescently tagged proteins. We show that PIFiA outperforms existing approaches for molecular representation learning and describe a range of downstream analysis tasks to explore the information content of the feature profiles. Specifically, we cluster extracted features into a hierarchy of functional organization, study cell population heterogeneity, and develop techniques to distinguish multi-localizing proteins and identify functional modules. Finally, we confirm new PIFiA predictions using a colocalization assay, suggesting previously unappreciated biological roles for several proteins. Paired with a fully interactive website (https://thecellvision.org/pifia/), PIFiA is a resource for the quantitative analysis of protein organization within the cell.
AIM (Angular Indication Measurement)- Visual Acuity: An adaptive, self-administered, and generalizable vision assessment method used to measure visual acuity
Authors: Skerswetat Jan , He Jingyi , Shah Jay Bijesh , Aycardi Nicolas , Freeman Michelle , Bex Peter John
Published: February 2023

This proof-of-concept study introduces Angular Indication Measurement and applies it to VA (AIM-VA). First, we compared the ability of AIM-VA and ETDRS to detect defocus and astigmatic blur in 22 normally-sighted adults. Spherical and cylindrical lenses (±0.00D, +0.25D, +0.50D, +0.75D, +1.00D, +2.00D and +0.50D, +1.00D, +2.00D each at 0°, 90°, 135°, respectively) in the dominant eye induced blur. Second, we compared repeatability over two tests of AIM-VA and ETDRS. A 2-way-ANOVA showed a main effect for defocus-blur and test with no interaction. A 3-way-ANOVA for the astigmatism experiment revealed main effects for test type, blur, and direction and with no interactions. Planned multiple comparisons showed AIM had greater astigmatic-induced VA loss than ETDRS. Bland-Altman plots showed small bias and no systematic learning effect for either test type and improved repeatability with >2 adaptive steps for AIM-VA. AIM-VA’s ability to detect defocus was comparable with that of an ETDRS letter chart and showed greater sensitivity to astigmatic blur, and AIM-VA’s repeatability is comparable with ETDRS when using 2 or more adaptive steps. AIM’s self-administered orientation judgment approach is generalizable to interrogate other visual functions, e.g., contrast, color, motion, stereo-vision.
Toxin/Antitoxin Systems Induce Persistence and Work in Concert with Restriction/Modification Systems to Inhibit Phage
Authors: Fernández-García Laura , Song Sooyeon , Kirigo Joy , Battisti Michael E. , Huelgas-Méndez Daniel , García-Contreras Rodolfo , Petersen Maiken E. , Tomás María , Wood Thomas K.
Published: February 2023

Myriad bacterial anti-phage systems have been described and often the mechanism of programmed cell death is invoked for phage inhibition. However, there is little evidence of ‘suicide’ under physiological conditions for these systems. Instead of death to stop phage propagation, we show here that persister cells, i.e., transiently-tolerant, dormant, antibiotic-insensitive cells, are formed and survive using theEscherichia coliC496_10 tripartite toxin/antitoxin system MqsR/MqsA/MqsC to inhibit T2 phage. Specifically, MqsR/MqsA/MqsC inhibited T2 phage by one million-fold and reduced T2 titers by 500-fold. During T2 phage attack, in the presence of MqsR/MqsA/MqsC, evidence of persistence include the single-cell physiological change of reduced metabolism (via flow cytometry), increased spherical morphology (via transmission electron microscopy), and heterogeneous resuscitation. Critically, we found restriction-modification systems (primarily EcoK McrBC) work in concert with the toxin/antitoxin system to inactivate phage, likely while the cells are in the persister state. Phage attack also induces persistence inKlebsiellaandPseudomonasspp. Hence, phage attack invokes a stress response similar to antibiotics, starvation, and oxidation, which leads to persistence, and this dormant state likely allows restriction/modification systems to clear phage DNA.
The axon guidance cue SEMA3A promotes the aggressive phenotype of basal-like PDAC
Authors: Lupo Francesca , Pezzini Francesco , Fiorini Elena , Adamo Annalisa , Veghini Lisa , Bevere Michele , Frusteri Cristina , Delfino Pietro , D’Agosto Sabrina , Andreani Silvia , Piro Geny , Malinova Antonia , De Sanctis Francesco , Pasini Davide , Lawlor Rita T. , Hwang Chang-il , Carbone Carmine , Amelio Ivano , Bailey Peter , Bronte Vincenzo , Tuveson David , Scarpa Aldo , Ugel Stefano , Corbo Vincenzo
Published: February 2023

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with few available therapeutic options. Two transcriptional cancer cell states have been consistently reported in PDAC, with the basal-like/squamous phenotype displaying a more aggressive biological behavior. Genetic and epigenetic dysregulation of the axon guidance pathway are common in PDAC, yet our understanding of its biological relevance is limited. Here, we investigated the functional role of the axon guidance cue SEMA3A in sustaining the progression of PDAC. We integrated available transcriptomic datasets of human PDAC within situhybridization analyses of patients’ tissues to find that SEMA3A is expressed by stromal cells and selectively enriched in epithelial cells of the basal-like/squamous subtype. We found that both cell-intrinsic and cell extrinsic factors instructing the basal-like/squamous subtype induce expression of SEMA3A in PDAC cells.In vitro, SEMA3A promoted cell migration as well as anoikis resistance. At molecular level, these phenotypes were associated with increased FAK signaling and enrichment of gene programs related to cytoskeleton remodeling. Accordingly, SEMA3A provided mouse PDAC cells with greater metastatic competence. In mouse orthotopic allografts, SEMA3A remodeled the TME by favoring infiltration of tumor-associated macrophages and exclusion of T cells. Mechanistically, SEMA3A functioned as chemoattractant for macrophages and favored their polarization towards an M2-like phenotype. In SEMA3Ahightumors, depletion of macrophages resulted in greater intratumor infiltration by CD8+ T cells and increased sensitivity of these tumors to chemotherapy. Overall, we show that SEMA3A contributes to the malignant phenotype of basal-like PDAC.
A top-down slow breathing circuit that alleviates negative affect
Authors: Jhang Jinho , Liu Shijia , O’Keefe David D. , Han Sung
Published: February 2023

Breathing is profoundly influenced by both behavior and emotion1–4and is the only physiological parameter that can be volitionally controlled4–6. This indicates the presence of cortical-to-brainstem pathways that directly control brainstem breathing centers, but the neural circuit mechanisms of top-down breathing control remain poorly understood. Here, we identify neurons in the dorsal anterior cingulate cortex (dACC) that project to the pontine reticular nucleus caudalis (PnC) and function to slow breathing rates. Optogenetic activation of this corticopontine pathway (dACC→PnC neurons) in mice slows breathing and alleviates behaviors associated with negative emotions without altering valence. Calcium responses of dACC→PnC neurons are tightly correlated with changes in breathing patterns entrained by behaviors, such as drinking. Activity is also elevated when mice find relief from an anxiety-provoking environment and slow their breathing pattern. Further, GABAergic inhibitory neurons within the PnC that receive direct input from dACC neurons decrease breathing rate by projecting to pontomedullary breathing centers. They also send collateral projections to anxiety-related structures in the forebrain, thus comprising a neural network that modulates breathing and negative affect in parallel. These analyses greatly expand our understanding of top-down breathing control and reveal circuit-based mechanisms by which slow breathing and anxiety relief are regulated together.
Specialized late cingulo-opercular network activation elucidates the mechanisms underlying decisions about ambiguity
Authors: Pierce Jordan E. , Petro Nathan M. , Clancy Elizabeth , Gratton Caterina , Petersen Steven E. , Neta Maital
Published: February 2023

Cortical task control networks, including the cingulo-opercular (CO) network play a key role in decision-making across a variety of functional domains. In particular, the CO network functions in a performance reporting capacity that supports successful task performance, especially in response to errors and ambiguity. In two studies testing the contribution of the CO network to ambiguity processing, we presented a valence bias task in which masked clearly and ambiguously valenced emotional expressions were slowly revealed over several seconds. This slow reveal task design provides a window into the decision-making mechanisms as they unfold over the course of a trial. In the main study, the slow reveal task was administered to 32 young adults in the fMRI environment and BOLD time courses were extracted from regions of interest in three control networks. In a follow-up study, the task was administered to a larger, online sample (n = 81) using a more extended slow reveal design with additional unmasking frames. Positive judgments of surprised faces were uniquely accompanied by slower response times and strong, late activation in the CO network. These results support the initial negativity hypothesis, which posits that the default response to ambiguity is negative and positive judgments are associated with a more effortful controlled process, and additionally suggests that this controlled process is mediated by the CO network. Moreover, ambiguous trials were characterized by a second CO response at the end of the trial, firmly placing CO function late in the decision-making process.
Partialin vivoreprogramming enables injury-free intestinal regeneration via autonomous Ptgs1 induction
Authors: Kim Jumee , Kim Somi , Lee Seung-Yeon , Jo Beom-Ki , Oh Ji-Young , Kwon Eun-Ji , Kim Keun-Tae , Adpaikar Anish Ashok , Kim Eun-Jung , Jung Han-Sung , Hong Chang Pyo , Kim Jong Kyoung , Koo Bon Kyoung , Cha Hyuk-Jin
Published: February 2023

Tissue regeneration after injury involves the dedifferentiation of somatic cells, a natural adaptive reprogramming process that leads to the emergence of injury-responsive cells with fetal-like characteristics in the intestinal epithelium. However, there is no direct evidence that adaptive reprogramming involves a shared molecular mechanism with direct cellular reprogramming. Here, we induced dedifferentiation of intestinal epithelial cells through forced partial reprogrammingin vivousing “Yamanaka factors” (Oct4, Sox2, Klf4, and c-Myc: OSKM). The OSKM-induced dedifferentiation showed similar molecular features of intestinal regeneration, including a rapid transition from homeostatic cell types to injury-responsive-like cell types. These injury-responsive-like cells, sharing a gene signature of revival stem cells and atrophy-induced villus epithelial cells, actively assisted tissue regeneration following ionizing radiation-induced acute tissue damage. In contrast to normal intestinal regeneration, which involves epi-mesenchymal crosstalk through induction ofPtgs2(encoding Cox2) upon injury, the OSKM expression promotes the autonomous production of prostaglandin E2 via epithelialPtgs1(encoding Cox1) expression. These results indicate that prostaglandin synthesis is a common mechanism for intestine epithelial regeneration but involves a different enzyme (Ptgs1for Cox1) when partial reprogramming is directly applied to the intestinal epithelium.
Historical demography and species distribution models shed light on past speciation in primates of northeast India
Authors: Trivedi Mihir , Arekar Kunal , Umapathy Govindhaswamy
Published: February 2023

Objectives

To ascertain the effect of historical demography and past climate change as the drivers of diversity in northeast India.

Materials and methods

We took the variant called whole genome files of nine species present in the northeast India from Primate genome sequencing consortium work and assessed each species historic effective population size by using Multiple Sequentially Markovian Coalescent (MSMC) tool. We also constructed species distribution models on past (Pliocene and Pleistocene) and present climate with Maxent, by utilizing publicly available distribution data for each species.

Results

We got the effective population sizes for 10 million years ago at most, though we considered the data only till 3.3 million years. All species showed rise and decline at various time periods. The species distribution models showed disparate distribution at all three time points with a genera-wise pattern emerging.

Discussion

We found that the evolutionary trajectories of all the four genera into consideration,Macaca, Trachypithecus, HoolockandNycticebusare different from each other. Species inMacacalooks to be evolved in northeast as well as come from southeast Asia. Some species ofTrachypithecusseems to radiated in the northeast India. Similarly,Hoolockhas evolved in the region andNycticebusis predicted have arrived from Indochina in the region. Hence, this study provides unique insights to the evolutionary dynamics for primate species in the northeast India.
INPP5D/SHIP1 regulates inflammasome activation in human microglia
Authors: Chou Vicky , Fancher Seeley B. , Pearse Richard V. , Lee Hyo , Lam Matti , Seyfried Nicholas T. , Bennett David A. , De Jager Phillip L. , Menon Vilas , Young-Pearse Tracy L.
Published: February 2023

Microglia and neuroinflammation are implicated in the development and progression of Alzheimer’s disease (AD). To better understand microglia-mediated processes in AD, we studied the function of INPP5D/SHIP1, a gene linked to AD through GWAS. Immunostaining and single nucleus RNA sequencing confirmed that INPP5D expression in the adult human brain is largely restricted to microglia. Examination of prefrontal cortex across a large cohort revealed reduced full length INPP5D protein levels in AD patient brains compared to cognitively normal controls. The functional consequences of reduced INPP5D activity were evaluated in human induced pluripotent stem cell derived microglia (iMGLs), using both pharmacological inhibition of the phosphatase activity of INPP5D and genetic reduction in copy number. Unbiased transcriptional and proteomic profiling of iMGLs suggested an upregulation of innate immune signaling pathways, lower levels of scavenger receptors, and altered inflammasome signaling with INPP5D reduction. INPP5D inhibition induced the secretion of IL-1ß and IL-18, further implicating inflammasome activation. Inflammasome activation was confirmed through visualization of inflammasome formation through ASC immunostaining in INPP5D-inhibited iMGLs, increased cleaved caspase-1 and through rescue of elevated IL-1ß and IL-18 with caspase-1 and NLRP3 inhibitors. This work implicates INPP5D as a regulator of inflammasome signaling in human microglia.