bluuebunny/crossref_metadata_2025 huggingface dataset:
Individual differences in music-induced interpersonal synchronization and self–other integration: the role of creativity and empathy
Authors: Kempf Adrian , Maes Pieter-Jan , Gener Canan , Schiavio Andrea
Published: November 2024

It has been demonstrated that moving together in synchrony to music makes us feel connected. Yet, little is known about the individual differences that shape the relationship between interpersonal synchronization to music and social bonding. The present research tests the hypothesis that this association is influenced by differences in empathy and creativity–two highly relevant factors in many musical activities. We implemented a synchronization task featuring a virtual drummer and measured self–other integration (SOI), a core component of social bonding. We employed a dual-measurement paradigm, incorporating both an explicit assessment (
Inclusion of Other in the Self
scale) and an implicit assessment (
joint-Simon effect
) of SOI. Surprisingly, our analysis did not reveal explicit and implicit measurements correlating, nor were they similarly affected by interpersonal synchronization. This raises questions about the assessment of SOI in interpersonal synchronization experiments. Furthermore, we observed no moderating role of empathy or creativity in the association between interpersonal synchronization and SOI. Nevertheless, we found creativity to correlate with SOI. In light of this finding, we recommend placing greater emphasis on creativity as a decisive factor in the study of musical interaction.
Prey detection by a stepwise visual template matching mechanism
Authors: Silverman Jules , Taylor Brad W.
Published: November 2024

Predators can improve prey capture using a search image, and recent prey provide a visual template with which subsequent prey are compared. Considering trout feeding responses to mayfly prey of different sizes and phenological availability across years, we tested if changing relative abundances (ratios) of prey of the same species, but different body sizes, shifted trout feeding behaviour. For example, we hypothesized that a feeding switch from larger to smaller prey required continuous exposure to the novel smaller prey. The hypothesis that continuous exposure to novel small prey results in their acceptance was not supported. Rather, we discovered that trout identify novel prey using a dynamic stepwise visual neural template prey matching process, which involves the formation of focal prey template based on size or type, rejection of novel prey that do not match the size or type templates and modification of the existing or development of multiple prey templates that eventually enabled recognition of novel, small prey. We also discovered trout store multiple visual prey templates in memory. These results have implications for predator and prey dynamics, optimal foraging, the persistence of rare prey, prey species coexistence and predator selection on prey phenology.
Evolutionary dynamics of voluntary vaccination for imperfect multi-efficacy vaccines
Authors: Hu Shusheng , Liu Yuan , Wu Bin
Published: November 2024

Voluntary vaccination is crucial for public health. The likelihood that the vaccinated get fully immune is typically referred to as the vaccine efficacy. In addition to this, the efficacy of vaccines also depends on inhibiting the transmission rates and protecting patients from critical symptoms. It has yet to be answered how the multi-efficacy of vaccines affects the vaccination behaviour. Here, we propose a game theoretical model of vaccination behaviour with a heterogeneous-transmission epidemiological process. Intuitively, individuals are likely to take vaccination for either high-efficient vaccines or epidemics with a large basic reproductive number. We find, however, a low economic discount rate can promote the uptake level for low-effectiveness vaccines and epidemics with small basic reproductive numbers. This result suggests that the perceived cost is more important than the risk of infection and the effectiveness of vaccines. In addition, we develop an analytical approximation to address the challenge arising from the coupled dynamics of vaccination and disease spread. This study shows how the interplay among three types of vaccine efficacies (transmission blocking, symptom mitigating and full immunity protecting) affects individual vaccination decisions and epidemic outcomes, and the model can be insightful for epidemic control.
A multi-agent system to dynamically devise an LCA framework weighting system taking into account socio-technical and environmental consideration
Authors: Ghoroghi Ali , Rezgui Yacine , Petri Ioan , Beach Thomas , Yeung Jonathan , Ghaemi Afrouz
Published: November 2024

This research article explores the need to adapt the weighting system of a life cycle assessment (LCA) framework to a wide range of socio-technical and environmental considerations, which are complex and sensitive to external stressors. The study demonstrates the potential of agent-based systems to adapt a weighting system to dynamic conditions, and suggests integrating an agent-based model to handle uncertainties of weighting in environmental impact assessment. Generative adversarial networks (GANs) and multi-agent systems (MAS) are utilized to address data limitations and simulate diverse scenarios. We confirm the potential of agent-based systems to analyse the effective management of uncertainties and customization of weighting systems in environmental impact assessments to improve decision making. Furthermore, the study emphasizes the importance of continuous adaptation and recalibration to ensure the system remains relevant in dynamic environments. The results confirm that MAS is a powerful tool for managing uncertainty, customizing weighting systems and improving decision making in environmental assessments. Moreover, the study acknowledges challenges and sets the groundwork for future research.
Linking deep-time subduction history to modern day expressions of dynamic topography
Authors: Calvelage C. M. , Wu Jonny , Colli Lorenzo , Lin Yi-An , Zheng Yingcai
Published: November 2024

Dynamic topography refers to vertical deflections of Earth’s surface from viscous flow within the mantle. Here we investigate how past subduction history affects present dynamic topography. We assimilate two plate reconstructions into TERRA forward mantle convection models to calculate past mantle states and predict Earth’s present dynamic topography; a comparison is made with a database of observed oceanic residual topography. The two assimilated plate reconstructions ‘Earthbyte’ and ‘Tomopac’ show divergent subduction histories across an extensive deep-time interval within Pacific-Panthalassa. We find that introducing an alternative subduction history perturbs our modelled present-day dynamic topography on the same order as the choice of radial viscosity. Additional circum-Pacific intra-oceanic subduction in Tomopac consistently produces higher correlations to the geoid (more than 20% improvement). At spherical harmonic degrees 1–40, dynamic topography models with intra-oceanic subduction produce universally higher correlations with observations and improve fit by up to 37%. In northeast Asia, Tomopac models show higher correlations (0.46 versus 0.18) to observed residual topography and more accurately predict approximately 1 km of dynamic subsidence within the Philippine Sea plate. We demonstrate that regional deep-time changes in subduction history have widespread impacts on the spatial distribution and magnitude of present-day dynamic topography. Specifically, we find that local changes to plate motion histories can induce dynamic topography changes in faraway regions located thousands of kilometres away. Our results affirm that present-day residual topography observations provide a powerful, additional constraint for reconstructing ancient subduction histories.
Propagation and non-reciprocity in time-modulated diffusion through the lens of high-order homogenization
Authors: Touboul Marie , Lombard Bruno , Assier Raphael C. , Guenneau Sebastien , Craster Richard V.
Published: November 2024

The homogenization procedure developed here is conducted on a laminate with periodic space–time modulation on the fine scale: at the leading order, this modulation creates convection in the low-wavelength regime if both parameters are modulated. However, if only one parameter is modulated, which is more realistic, this convective term disappears and one recovers a standard diffusion equation with effective homogeneous parameters; this does not describe the non-reciprocity and the propagation of the field observed from exact dispersion diagrams. This inconsistency is corrected here by considering second-order homogenization that results in a non-reciprocal propagation term that is proved to be non-zero for any laminate and verified via numerical simulation. The same methodology is also applied to the case when the density is modulated in the heat equation, leading, therefore, to a corrective advective term that cancels out non-reciprocity at the leading order but not at the second order.
Inferring the locomotor ecology of two of the oldest fossil squirrels: influence of operationalization, trait, body size and machine learning method
Authors: Wölfer Jan , Hautier Lionel
Published: November 2024

Correlations between morphology and lifestyle of extant taxa are useful for predicting lifestyles of extinct relatives. Here, we infer the locomotor behaviour of
Palaeosciurus goti
from the middle Oligocene and
Palaeosciurus feignouxi
from the lower Miocene of France using their femoral morphology and different machine learning methods. We used two ways to operationalize morphology, in the form of a geometric morphometric shape dataset and a multivariate dataset of 11 femoral traits. The predictive models were built and tested using more than half (180) of the extant species of squirrel relatives. Both traditional models such as linear discriminant analysis and more sophisticated models like neural networks had the greatest predictive power. However, the predictive power also depended on the operationalization and the femoral traits used to build the model. We also found that predictive power tended to improve with increasing body size. Contrary to previous suggestions, the older species,
P. goti
, was most likely arboreal, whereas
P. feignouxi
was more likely terrestrial. This provides further evidence that arboreality was already the most common locomotor ecology among the earliest squirrels, while a predominantly terrestrial locomotor behaviour evolved shortly afterwards, before the vast establishment of grasslands in Europe.
Migratory birds can extract positional information from magnetic inclination and magnetic declination alone
Authors: Packmor Florian , Kishkinev Dmitry , Zechmeister Thomas , Mouritsen Henrik , Holland Richard A.
Published: November 2024

Migratory birds are able to navigate over great distances with remarkable accuracy. The mechanism they use to achieve this feat is thought to involve two distinct steps: locating their position (the ‘map’) and heading towards the direction determined (the ‘compass’). For decades, this map-and-compass concept has shaped our perception of navigation in animals, although the nature of the map remains debated. However, some recent studies suggest the involvement of the Earth’s magnetic field in the map step. Here, we tested whether migratory songbirds, Eurasian reed warblers (
Acrocephalus scirpaceus
), can determine their position based on two magnetic field components that are also associated with direction finding, i.e. magnetic inclination and magnetic declination. During a virtual magnetic displacement experiment, the birds were exposed to altered magnetic inclination and magnetic declination values that would indicate a displacement from their natural migratory corridor, but the total intensity of the field remained unchanged, creating a spatial mismatch between these components. The response was a change in the birds’ migratory direction consistent with a compensatory re-orientation. This suggests that birds can extract positional as well as directional information from these cues, even when they are in conflict with another component of the magnetic field. It remains to be seen whether birds use the total intensity of Earth’s magnetic field for navigation.
Cryptic diversity patterns of subterranean estuaries
Authors: Calderón-Gutiérrez Fernando , Labonté Jessica M. , Gonzalez Brett C. , Iliffe Thomas M. , Mejía-Ortíz Luis M. , Borda Elizabeth
Published: November 2024

Subterranean estuaries are coastal ecosystems characterized by vertically stratified groundwater. The biota within these ecosystems is relatively understudied due to the inherent difficulty of accessing such extreme environments. The fauna inhabiting these ecosystems is considered vulnerable to extinction, and the presence of cryptic species has major implications for research and conservation efforts. Most species lack molecular data; however, the evaluation of genetic data for some taxa has revealed that undocumented species are common. This study employs molecular species delimitation methods and DNA barcoding through the analysis of publicly and newly generated sequences, including individuals from type localities and non-crustacean phyla; the latter are typically overlooked in biodiversity assessments of subterranean estuaries. We analysed 376 cytochrome c oxidase subunit I (COI) gene sequences and 154 16S rRNA gene sequences. The COI sequences represented 32% of previously described species and 50% of stygobiont species from the Yucatan Peninsula and Cozumel Island, while sequences of the 16S rRNA represented 14% of described species and 22% of stygobionts. Our results revealed cryptic genetic lineages and taxonomic misidentification of species. As several species from these ecosystems are recognized as endangered, the use of molecular approaches will improve biodiversity estimates and highlight overlooked cryptic lineages in need of evaluation of conservation status.
Stress in the social environment: behavioural and social consequences of stress transmission in bird flocks
Authors: Brandl Hanja B. , Farine Damien R.
Published: November 2024

The stress response helps individuals cope with challenges, yet how individual stress levels shape group-level processes and the behaviour of other group members has rarely been explored. In social groups, stress responses can be buffered by others or transmitted to members that have not even experienced the stressor first-hand. Stress transmission, in particular, can have profound consequences for the dynamics of social groups and the fitness of individuals therein. We experimentally induced chronic stress within replicated colonies of zebra finches and used fine-scale tracking to observe the consequences of stress-exposed colony members for the behaviour and reproduction of non-manipulated colony members. Non-manipulated individuals in colonies containing stress-exposed individuals exhibited reduced activity, and fewer—but more differentiated—social bonds. These effects were stronger in colonies with a greater proportion of stress-treated individuals, demonstrating that the impact of stressors can reach beyond directly exposed individuals by also affecting their group mates. We found no evidence that socially transmitted stress affected reproduction or long-term physiological measurement in unmanipulated birds, even though the stress-exposed demonstrators laid slightly fewer eggs and showed stressor-dependent changes in feather corticosterone. Social transmission of these effects, if occurring at all, might be more subtle.
Cities beyond proximity
Authors: Hill Dan , Bruno Matteo , Melo Hygor P. M. , Takeuchi Yuichiro , Loreto Vittorio
Published: November 2024

The concept of ‘proximity-based cities’ has gained attention as a new urban organizational model. Most prominently, the 15-minute city contends that cities can function more effectively, equitably and sustainably if essential, everyday services and key amenities are within a 15-minute walk or cycle. However, focusing solely on travel time risks overlooking disparities in service quality, as the proximity paradigm tends to emphasize the mere presence of an element in a location rather than bringing up more complex questions of identity, diversity, quality, value or relationships. Transitioning to value-based cities by considering more than just proximity can enhance local identity, resilience and urban democracy. Fostering bottom–up initiatives can create a culture of local care and value, while predominantly top–down governing strategies can lead to large inequalities. Balancing these approaches can maximize resilience, health and sustainability. This equilibrium has the potential to accompany sustainable growth, by encouraging the creation of innovative urban solutions and reducing inequalities.

This article is part of the theme issue ‘Co-creating the future: participatory cities and digital governance’.
Functional segregation of cortical hand and speech areas by frequency detuning of an intrinsic motor rhythm
Authors: Anastasopoulou Ioanna , Cheyne Douglas O , Johnson Blake W
Published: November 2024

Many decades after Penfield’s (1937) classic depiction of the motor homunculus, it remains unclear how spatially contiguous and interconnected representations within human sensorimotor cortex might separate their activities to achieve the directed and precise control of distinct body regions evident in activities as different as typing and speaking. One long-standing but relatively neglected explanation draws from models of simple physical systems (like swinging pendulums) to posit that small differences in the oscillatory properties of neuronal populations (termed “frequency detuning”) can result in highly effective segregation of their activities and outputs. We tested this hypothesis by comparing the peak frequencies of beta-band (13-30 Hz) motor rhythms measured in a magnetoencephalographic neuroimaging study of finger and speech movements in a group of healthy adults and a group of typically developing children. Our results confirm a peak frequency task difference of about 1.5 Hz in the beta motor rhythms of both left and right hemispheres in adults. A comparable task difference was obtained in children for the left but not for the right hemisphere. These results provide novel support for the role of frequency detuning in the functional organisation of the brain and suggest that this mechanism should play a more prominent role in current models of bodily representations and their development within the sensorimotor cortex.

NEW & NOTEWORTHY

This work is the first evidence for frequency detuning of an intrinsic motor rhythm in spatially contiguous regions of primary motor cortex associated with hand and speech movements, supporting a mechanism of functional segregation that has been largely overlooked by current models of motor cortex organization. Our results from children further provide the first evidence for frequency detuning in the developing brain, indicating an early-developing mechanism with later refinements of hemispheric control.
Mapping atherogenesis mechanisms in smooth muscle cells by targeting genes linked to coronary artery disease
Authors: Albarrán-Juárez Julián , Markov Anton , Jensen Anne Louise , Møller Peter Loof , Uryga Anna K. , Djordjevic Djordje , Hansen Jakob , Jensen Lise Filt , Sharysh Diana , Pyke Charles , Moreno Jaime , Borghetti Giulia , Bachmann Julian , Herum Kate , Røge Lisa Maria , Traylor Matthew , Nyberg Michael , Nyegaard Mette , Bentzon Jacob Fog
Published: November 2024

Recent genome-wide association studies (GWAS) have identified multiple vascular cell-expressed genes linked to coronary artery disease (CAD), suggesting that smooth muscle cells (SMCs) and SMC-derived metaplastic cells are promising targets for novel antiatherosclerosis therapies. However, the disease-promoting pathways of most GWAS-identified genes are unknown, hindering their translation into therapeutic targets. This study integrated public GWAS data for CAD and single-cell RNA sequencing (scRNA-seq) analyses of human atherosclerotic plaques to identify 20 GWAS risk genes with a putative mechanism of action in SMCs or SMC-derived cells.

Gene perturbation experiments in SMCs coaxed to plaque-relevant phenotypes revealed that the selected risk genes, despite encoding very different types of proteins, regulated shared sets of genes associated with contractile functions, cell cycle pathways, NFκB, and type I interferon signaling. By integrating information about GWAS gene effect direction and a deep analysis of cholesterol- and stretch-induced gene modules in SMCs, we find evidence that cholesterol-induced signaling is a pro-atherogenic disease mechanism in SMCs that is upregulated by detrimental and downregulated by protective GWAS genes.

Overall, our study identifies a set of candidate disease mechanisms in SMCs that are regulated by multiple GWAS genes across several SMC assays. Furthermore, it provides proof-of-concept for using GWAS gene effect directionality to predict the pathogenic effect of candidate disease mechanisms that can be extended to other GWAS genes and cell types in the future.
Deciphering Memory Patterns in Eco-Epidemiological systems through the lens of BaFOMS: A Bayesian Fractional Order Model Selection Method
Authors: Mestry Dipali Vasudev , Singh Pratik , Rocklöv Joacim , Bhowmick Amiya Ranjan
Published: November 2024

The evolution of eco-epidemiological systems is significantly influenced by the memory or previous history of the system. These non-Markovian dynamics are effectively modelled using fractional derivatives (FDs), incorporating memory kernels that reflect long-term or short-term memory characteristics in corresponding nonlinear fractional differential evolution equations. We introduce BaFOMS, a framework for identifying and selecting the optimal FD model for eco-epidemiological processes based on historical data. Specifically, we evaluate a class of fractional logistic growth models defined by their time correlation functions and determine the optimal model through Bayesian inference, selecting the one with the highest posterior probability. We also demonstrated BaFOMS efficiency in parameter estimation and forecasting, producing reliable results with quantified uncertainties. The method is shown to be robust across a range of eco-epidemiological datasets, offering computational efficiency and reliable inference about the evolution dynamics.
Maternal exercise alters placental proteome in an exercise mode-specific manner
Authors: Jevtovic Filip , Wisseman Breanna , Jahan Fahmida , Claiborne Alex , Collier David N. , DeVente James E. , Mouro Steven , Zeczycki Tonya , Goodyear Laurie J. , May Linda E.
Published: November 2024

Maternal exercise is a widely recommended and safe intervention associated with the improvement of maternal gestational and infant metabolic health. While various modes of exercise are deemed safe during pregnancy, the effects of supervised maternal aerobic, resistance, and combination (aerobic+resistance) exercise remain understudied. Specifically, it remains unknown how different modes of maternal exercise affect the placenta, an organ central to maternal-fetal communication and successful pregnancy outcomes. This study aimed to characterize the placental proteomic changes in response to controlled and supervised maternal exercise during gestation. Results showed that the placental proteomic landscape changes in an maternal exercise mode-specific way. Additionally, proteomics revealed that ∼20% of the identified placental proteins were associated with maternal exercise volume during gestation. These results highlight the differential effect maternal exercise modes have on the placental proteome and further implicate the placenta in mediating the effects of maternal exercise on maternal and infant health.
The adaptive landscapes of three globalEscherichia colitranscriptional regulators
Authors: Antunes Westmann Cauã , Goldbach Leander , Wagner Andreas
Published: November 2024

The evolution of new gene regulation is an important source of evolutionary adaptations and innovations, especially when organisms encounter new environments. At its heart is the process by which new and strong DNA binding sites of transcription factors (TFs) originate in evolution. Here we study the potential of Darwinian evolution to create strong binding sites for the threeEscherichia coliglobal transcription factors CRP, Fis, and IHF. Using a massively parallel reporter assay, we measure for each TF the ability of more than 30,000 binding sites to regulate gene expression. We use the resulting data to map the adaptive landscape of each TF. We find that all three landscapes are rugged, epistatic, and harbor multiple peaks. The highest peaks are widely scattered throughout the landscape, indicating that strong regulation can be achieved by very different binding sites. Landscape ruggedness does not prevent the evolution of strong regulation, because more than 10% of evolving populations can attain one of the highest peaks. Adaptive evolution starting from the same DNA sequence can attain more than one high peak, and some high peaks are more likely to be reached than others. Our experiments show that de novo adaptive evolution of new gene regulation is feasible. It is also subject to a blend of chance, historical contingency, and evolutionary biases that favor some peaks and evolutionary paths over others.
Opposing Regulation of TNF Responses and IL-1β+ Macrophages by PGE2-cAMP and IFN-γ Signaling
Authors: Sokhi Upneet K. , Mishra Bikash , Yuan Ruoxi , Chinenov Yuri , Singaraju Anvita , Chan Karmela K. , Bass Anne R. , Donlin Laura , Ivashkiv Lionel B.
Published: November 2024

IL-1β-expressing macrophages have been described in rheumatoid arthritis (RA), immune checkpoint inhibitor-induced inflammatory arthritis (ICI-arthritis), and pancreatic cancer and proposed to be pathogenic. In RA and pancreatic cancer IL-1β+ macrophages express a TNF+PGE2 (TP) gene expression signature induced by cooperation between PGE2 and TNF signaling, but mechanisms that induce these cells and the extent to which they contribute to arthritic phenotypes are not known. In this study we used an integrated transcriptomic and epigenomic analysis in primary human monocytes to study PGE2-TNF crosstalk, and how it is regulated by IFN-γ, as occurs in RA synovial macrophages. We identified a (TNF + PGE2)- induced gene expression signature that is enriched in an IL1β+ RA macrophage subset defined by scRNAseq and includes genes in pathogenic IL-1, Notch and neutrophil chemokine pathways. A similar gene expression signature was apparent in an IL-1β+ macrophage subset newly identified by scRNAseq in ICI-arthritis. TP signature genes are distinct from canonical inflammatory NF-κB target genes such asTNF,IL6andIL12Band are activated by cooperation of PGE2-induced AP-1, CEBP and NR4A family transcription factors with TNF-induced NF-κB activity. Unexpectedly, IFN-γ suppressed induction of AP-1, CEBP and NR4A activity to ablate induction of IL-1, Notch and neutrophil chemokine genes, while promoting expression of distinct inflammatory genes such asTNFand T cell chemokines like CXCL10. These results reveal the basis for synergistic induction of inflammatory genes by PGE2 and TNF, and a novel regulatory axis whereby IFN-γ and PGE2 oppose each other to determine the balance between two distinct TNF-induced inflammatory gene expression programs relevant for RA and ICI-arthritis.
Surface remodeling and inversion of cell-matrix interactions underlies community recognition and dispersal inVibrio choleraebiofilms
Authors: Moreau Alexis , Nguyen Danh T. , Hinbest Alex , Zamora Anthony , Weerasekera Ranjuna , Matej Katherine , Zhou Xuening , Sanchez Sandra , Brenes Ignacio Rodriguez , Tai Jung-Shen Benny , Nadell Carey D. , Ng Wai-Leung , Gordon Vernita , Komarova Natalia L. , Olson Rich , Li Ying , Yan Jing
Published: November 2024

Biofilms are ubiquitous surface-associated bacterial communities embedded in an extracellular matrix. While it is commonly assumed that biofilm-dwelling cells are glued together by the matrix, how the cell-matrix interaction depends on the specific biochemistry of the matrix components and how this interaction varies during biofilm growth remains unclear. Here, we investigated cell-matrix interactions inVibrio cholerae(Vc), the causative agent of cholera. We combine genetics, microscopy, simulation, and biochemical tools to show thatVccells are not attractive toVibriopolysaccharide (VPS), the main matrix component, but they can be bridged with each other and to the VPS network through crosslinking by Bap1. Downregulation of VPS and surface trimming by the polysaccharide lyase RbmB cause surface remodeling as biofilms age, shifting the nature of cell-matrix interactions from attractive to repulsive and facilitating cell dispersal as aggregated groups. Our results suggest a new conceptual model in understanding the intricate cell-matrix interaction as the major driver for biofilm development, which is potentially generalizable to certain other biofilm-forming species and exopolysaccharides.
Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state
Authors: Rominger Mary C. , Gupta Saksham , Moorthi Sitapriya , McSharry Maria , Kamlapurkar Shriya , O’Brien Siobhan , Waldum Annie , Lo April , Duke Fujiko , Lowe Amy R. , Cromwell Elizabeth , Glabman Raisa , Koehne Amanda , Berger Alice H.
Published: November 2024

The discovery of oncogene addiction in cancer has led to the development of over a dozen FDA-approved biomarker-driven therapies in lung adenocarcinoma. Somatic mutations of the “Ras-like in all tissues” (RIT1) gene are non-canonical driver events in lung cancer, occurring in ∼2% of lung adenocarcinomas in a mutually exclusive fashion withKRASandEGFRmutations. Patients withRIT1-mutant lung cancer lack targeted therapy treatment options, and a lack of pre-clinical models has hindered the development of therapeutic strategies forRIT1-mutant lung cancer. Here we report a new mouse model of RIT1-driven lung cancer in which the human RIT1M90Ivariant can be induced in a Cre-regulated manner. We show that autochthonous expression of RIT1M90Iin the lung weakly promotes cancer alone or in combination with loss of thep53tumor suppressor. However, potent synergy between RIT1M90Iand inactivation ofNf2drives an aggressive epithelial-to-mesenchymal (EMT) lung cancer with 100% penetrance and short latency. We show this oncogenic cooperation is driven by synergistic activation of cJUN, a component of the AP-1 complex. Therapeutic inhibition of MEK and YAP/TEAD suppressed RIT1-driven lung cancer in vivo. These data identify YAP/TEAD as an important mediator of RIT1’s oncogenic potential and nominate TEAD as an important drug target inRIT1-mutant lung cancer.

HIGHLIGHTS

We report a new RIT1M90I-mutant autochthonous lung tumor model

The most common oncogenic variant of RIT1, RIT1M90I, weakly promotes lung tumor development

RIT1M90Idrives the formation of lethal lung tumors in cooperation withp53andNf2tumor suppressor gene loss

RIT1M90Iand YAP cooperatively regulate cJUN expression

Therapeutic MEK and TEAD targeting suppresses RIT1M90I-driven tumorigenesis
Improving the Capstone Biochemistry Lab and Evolution to a Course-Based Undergraduate Research Experience: Lessons Learned from the COVID-19 Online Modality
Authors: Rascón Alberto A.
Published: November 2024

The restructuring of an upper division biochemistry lab capstone course intended for biochemistry students with a range of laboratory experience was explored. A goal of the course was to give students practice with necessary skills in biochemical and biological techniques, especially for an entry level general position in biotechnology. The immediate impact of the online capstone course mandated by the COVID-19 pandemic limited students on learning essential hands-on research skills but evolved during the transition back to in-person instruction to include more elements of in-person practice. This article highlights the evolution of the capstone biochemistry lab to an in-person CURE capstone lab, with lessons learned and resources successfully used during the COVID-19 remote course. These include changes in the way information was disseminated, access to online resources, and modifications in student assessments. This article documents how course evolution resulted in a shift in pedagogical strategies leading to building a community of biochemistry learners that could be used to help college faculty in developing a CURE capstone lab.
Lysosomes cell autonomously regulate myeloid cell states and immune responses
Authors: Tejwani Leon , Balak Christopher , Skuja Lukas L. , Tatarakis David , Rana Anil , Fitzgerald Gabriel A. , Ha Connie , Lunkes de Melo Gabrielly , Sun Elizabeth W. , Heffner Catherine M. , Simon Matthew J. , Dugas Jason C. , Sarrafha Lily , Liang Eric , Sandmann Thomas , Glass Christopher K. , Di Paolo Gilbert
Published: November 2024

Myeloid cells maintain tissue homeostasis via the recognition, engulfment, and lysosomal clearance of dying cells and cellular debris, which is often accompanied by changes from homeostatic to reactive states. While a role for phagocytic receptors in gating these transitions has been described1,2, less is known about if and how lysosomes can contribute to transcriptional and functional plasticity. To determine how lysosomal health impacts myeloid cell states, we evaluated microglia and macrophages deficient for progranulin (encoded byGrn), a lysosomal protein with pleiotropic functions whose loss is associated with several neurodegenerative diseases3–8. Single-cell RNA-sequencing of the aged mouse brain identified aGrnknockout (KO)-specific microglial subpopulation marked by high GPNMB expression that displays hallmarks of lysosomal dysfunction, including lipofuscin accumulation. Epigenetic analysis of aged microglia revealed MITF/TFE transcription factors as key mediators of the transcriptional states associated withGrndeficiency. In addition to identifying a core myeloid cell transcriptional response to diverse lysosomal stressors, targeted perturbations of various lysosomal propertiesin vitrouncovered a cell autonomous, TREM2- independent, response to lysosomal deacidification (via v-ATPase or VPS34 loss of function) that overlaps withGrnKO microglia phenotypes, including the induction of a lysosomal gene program, increased proliferation, and secretion of pro-inflammatory cytokines. Compound loss-of-function approaches established GPNMB upregulation upon lysosomal stress is required for the compensatory response to enhance lysosomal function via promoting acidification. Finally, pharmacological endolysosomal reacidification through sodium/proton exchanger inhibition partially rescuedGrnKO microglia phenotypes. Overall, these data establish a fundamental link between lysosomal health and myeloid cell epigenetic, transcriptional, and functional states observed in neurodegeneration models.
Investigating Protein Degradability through Site-Specific Ubiquitin Ligase Recruitment
Authors: Shade Olivia , Ryan Amy , Belsito Gabriella , Deiters Alexander
Published: November 2024

We report targeted protein degradation through the site-specific recruitment of native ubiquitin ligases to a protein of interest via conjugation of E3 ligase ligands. Direct comparison of degradation ability of proteins displaying the corresponding bioconjugation handle at different regions of protein surfaces was explored. We demonstrate the benefit of proximal lysine residues and investigate flexibility in linker length for the design of optimal degraders. Two proteins without known small molecule ligands, EGFP and DUSP6, were differentially degraded when modified at different locations on their protein surfaces. Further, the cereblon-mediated degradation of the known PROTAC target ERRα was improved through the recruitment of the E3 ligase to regions different from the known ligand binding site. This new methodology will provide insight into overall protein degradability, even in the absence of a known small molecule ligand and inform the process of new ligand and PROTAC development to achieve optimal protein degradation. Furthermore, this approach represents a new, small molecule-based conditional OFF switch of protein function with complete genetic specificity. Importantly, the protein of interest is only modified with a minimal surface modification (< 200 Da) and does not require any protein domain fusions.
Factors affecting antenatal corticosteroid use in low- and middle-income countries: facility characteristics, structural readiness, and past performance of CEmONC signal functions
Authors: Yang Wen-Chien , Arsenault Catherine , Fan Victoria Y. , Ali Nazia Binte , Alwy Al-beity Fadhlun Mohamed , Smith Emily R.
Published: November 2024

Background

Antenatal corticosteroids (ACS) utilization is disproportionately limited in low- and middle-income countries where most global preterm newborns who could benefit from this intervention are born. Understanding the factors affecting ACS use is crucial for improving its uptake. This study aimed to investigate facility-level factors associated with ACS use in low-resource countries.

Methods

We used data from ten Service Provision Assessment surveys across nine countries. We restricted the sample to facilities that provided delivery services. Our primary outcome was recent ACS use, defined as having administered ACS within the past three months before the survey. We conducted mixed-effect log binomial regressions, with country as a fixed effect and sub-national regions as random intercepts, to explore the association between recent ACS use and facility characteristics, injectable corticosteroids and ultrasound availability, facility structural readiness, and past performance of nine Comprehensive Emergency Obstetric and Newborn Care (CEmONC) signal functions.

Results

This study included 6183 facilities from nine countries. Across eight countries with nationally representative data, only 22.7% (median, range 4.0% to 27.4%) of facilities that provided delivery services had used ACS recently. Urban facilities had a 21% higher likelihood of recent ACS use (95% CI 6%–38%) than rural facilities. Corticosteroid availability was associated with a 14% higher likelihood of recent ACS use (95% CI 1%–29%). Facilities in the highest readiness tertile were more likely to have recent ACS use than those in the lowest (RR 1.91, 95% CI 1.58–2.30). Each CEmONC signal function, except for assisted vaginal deliveries, was significantly associated with recent ACS use, with neonatal resuscitation having the largest effect (RR 2.62, 95% CI 1.93–3.55).

Conclusion

Facilities that had performed CEmONC services were more likely to administer ACS, highlighting the importance of provider knowledge, skills, and competence in managing obstetric and newborn emergencies for effective ACS provision.
Targeted pre-conditioning and cell transplantation in the murine lower respiratory tract
Authors: Kohn Anat , Herriges Michael J. , Basak Payel , Ma Liang , Thapa Bibek R. , Kotton Darrell N. , Hawkins Finn J.
Published: November 2024

Transplantation of airway basal stem cells could achieve a durable cure for genetic diseases of the airway, such as cystic fibrosis and primary ciliary dyskinesia. Recent work demonstrated the potential of primary- and pluripotent stem cell (PSC)-derived basal cells to efficiently engrai into the mouse trachea aier injury. However, there are many hurdles to overcome in translating these approaches to humans including developing safe and efficient methods for delivery in larger animal models. We propose a model which targets preconditioning and cell-delivery to the intrapulmonary airways utilizing a micro- bronchoscope for delivery. The detergent polidocanol was adapted for distal lung pre-conditioning, inducing intrapulmonary airway epithelial denudation by 5 and 24-hours post-delivery. While initial re- epithelialization of airways occurred later than tracheas, complete repair was observed within 7-days. Both PSC-derived and primary basal cells delivered via micro-bronchoscope post-polidocanol injury engraied in tracheas and intrapulmonary airways, respectively. Transplanted cells differentiated into ciliated and secretory lineages while maintaining a population of basal cells. These findings demonstrate the utility of bronchoscopically targeted pre-conditioning and cell delivery to the conducting intra- pulmonary airways, providing an important framework for pre-clinical translation of approaches for engineered airway epithelial regeneration.
Single nucleotide switches confer bacteriophage resistance toPseudomonas protegens
Authors: Vacheron Jordan , Heiman Clara M. , Keel Christoph
Published: November 2024

Phage therapy offers a promising strategy against bacterial pathogens in medicine and agriculture, but the rise of phage-resistant bacteria presents a significant challenge to its sustainability. Here, we used an environmental model bacterium,Pseudomonas protegensCHA0, to investigate phage resistance mechanisms in laboratory conditions through genomic analysis of four phage-resistant variants (C2, C4, C17, C18). Whole-genome sequencing revealed frequent deletions, insertions, and single nucleotide substitutions, particularly in genes encoding enzymes involved in cell surface modifications. The T428P mutation in AlgC, a phosphoglucomutase, and the P229T substitution in YkcC, a glycosyltransferase, each conferred resistance by potentially altering phage receptor accessibility while preserving bacterial fitness. These findings suggest that subtle mutations in surface-modifying enzymes enable phage resistance by modifying phage-receptor accessibility while maintaining bacterial growth, highlighting adaptive mechanisms in bacterial phage interactions. Further structural analysis is needed to fully understand these mutation-driven resistance mechanisms.
Metabolic insights into microbially induced calcite formation by Bacillaceae for application in bio-based construction materials
Authors: Seidel Michael , Hamley-Bennett Charlotte , Reeksting Bianca J. , Bagga Manpreet , Hellmann Lukas , Hoffmann Timothy D. , Kraemer Christiane , Ofiţeru Irina Dana , Paine Kevin , Gebhard Susanne
Published: November 2024

Microbially induced calcite precipitation (MICP) offers promising solutions for sustainable, low-cement infrastructure materials. While it is known how urea catabolism leads to biomineralization, the non-ureolytic pathways of MICP are less clear. This limits the use of the latter in biotechnology, despite its clear benefit of avoiding toxic ammonia release. To address this knowledge gap, the present study explored the interdependence between carbon source utilization and non-ureolytic MICP. We show that acetate can serve as the carbon source driving calcite formation in several environmental Bacillaceae isolates. This effect was particularly clear in aSolibacillus silvestrisstrain, which could precipitate almost all provided calcium when provided with a 2:1 acetate-to-calcium molar ratio, and we show that this process was independent of active cell growth. Genome sequencing and gene expression analyses revealed an apparent link between acetate catabolism and calcite precipitation in this species, suggesting MICP may be a calcium stress response.

Development of a simple genetic system forS. silvestrisled to deletion of a proposed calcium binding protein, although this showed minimal effects on MICP. Taken together, this study provides insights into the physiological processes leading to non-ureolytic MICP, paving the way for targeted optimization of biomineralization for sustainable materials development.
Sigma factors as potential targets to enhance recombinant protein expression
Authors: Pohlen Laura , García Emily , Martínez Luz María , Flores Noemí , Büchs Jochen , Gosset Guillermo , Lara Alvaro R.
Published: November 2024

The transcriptional factors control the expression of many genes and represent an important layer of complexity in cell factories. However, the effect of individual sigma factor deletions from a biomanufacturing perspective has not been addressed. In this contribution, growth and oxygen consumption ofE. coliBW25113 strains with individual inactivation of each sigma factor were characterized under various conditions. The deletion ofrpoDhas been reported to be lethal forE. coli. However, the evaluatedrpoDmutant did not exhibit major growth defects in the mineral medium and is explained because therpoDgene is duplicated in this strain. Recombinant protein was expressed at three different induction levels in a mineral and LB media. ThefliAmutant was the best producer in the mineral medium, whereas therpoDmutant overperformed the other strains in LB medium. This suggest that a lowerrpoDgene dosage is positive for the performance of the cell factory in complex medium. In cultures at 20 °C, therpoSmutant exhibited the greatest recombinant expression. To our knowledge, this is the first systematic study evaluating the potential of sigma factor deletion for improving recombinant protein production.
In silico analysis of metabolic burden effects on a multicellular integral controller
Authors: Campanile Giovanni , Martinelli Vittoria , Salzano Davide , Fiore Davide , di Bernardo Mario
Published: November 2024

Metabolic burden is a critical limiting factor in the design of synthetic circuits, affecting both their reliability and performance. To mitigate its effects, distributing control functions across different cell populations within a multicellular control architecture offers a promising solution, while simultaneously enhancing modularity and re-usability of the circuits. We first present a model that explicitly accounts for limited ribosome availability within cells. Using this framework, we then derive a mathematical model of a multicellular antithetic integral controller that incorporates these shared resources. Through numerical bifurcation analysis andin silicoagent-based experiments in BSim, we compare the multicellular controller against its traditional single-cell (embedded) implementation, evaluating both resource utilization and stability.
Structure of an Archaeal Ribosome with a Divergent Active Site
Authors: Nissley Amos J. , Shulgina Yekaterina , Kivimae Roan W. , Downing Blake E. , Penev Petar I. , Banfield Jillian F. , Nayak Dipti D. , Cate Jamie H. D.
Published: November 2024

The ribosome is the universal translator of the genetic code and is shared across all life. Despite divergence in ribosome structure over the course of evolution, the peptidyl transferase center (PTC), the catalytic site of the ribosome, has been thought to be nearly universally conserved. Here, we identify clades of archaea that have highly divergent ribosomal RNA sequences in the PTC. To understand how these PTC sequences fold, we determined cryo-EM structures of thePyrobaculum calidifontisribosome. We find that sequence variation leads to the rearrangement of key PTC base triples and differences between archaeal and bacterial ribosomal proteins also enable sequence variation in archaeal PTCs. Finally, we identify a novel archaeal ribosome hibernation factor that differs from known bacterial and eukaryotic hibernation factors and is found in multiple archaeal phyla. Overall, this work identifies factors that regulate ribosome function in archaea and reveals a larger diversity of the most ancient sequences in the ribosome.