bluuebunny/crossref_metadata_2025 huggingface dataset:
Anchoring the mean generation time in the SEIR to mitigate biases in ℜ
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estimates due to uncertainty in the distribution of the epidemiological delays
Authors: Andrade Jair , Duggan Jim
Published: August 2023

The basic reproduction number,

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, is of paramount importance in the study of infectious disease dynamics. Primarily,

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serves as an indicator of the transmission potential of an emerging infectious disease and the effort required to control the invading pathogen. However, its estimates from compartmental models are strongly conditioned by assumptions in the model structure, such as the distributions of the latent and infectious periods (epidemiological delays). To further complicate matters, models with dissimilar delay structures produce equivalent incidence dynamics. Following a simulation study, we reveal that the nature of such equivalency stems from a linear relationship between

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and the mean generation time, along with adjustments to other parameters in the model. Leveraging this knowledge, we propose and successfully test an alternative parametrization of the SEIR model that produces accurate

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estimates regardless of the distribution of the epidemiological delays, at the expense of biases in other quantities deemed of lesser importance. We further explore this approach’s robustness by testing various transmissibility levels, generation times and data fidelity (overdispersion). Finally, we apply the proposed approach to data from the 1918 influenza pandemic. We anticipate that this work will mitigate biases in estimating

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0

.
Conditionally integrable PDEs, non-classical symmetries and applications
Authors: Broadbridge Philip , Bradshaw-Hajek Bronwyn H. , Hutchinson Ashleigh J.
Published: August 2023

Some multi-dimensional nonlinear partial differential equations reduce to a linear equation in fewer dimensions after imposing one additional constraint. A large class of useful conditionally integrable reaction–diffusion equations follows from a single non-classical symmetry reduction, yielding an infinite-dimensional but incomplete solution space. This solution device extends further to other nonlinear equations such as higher-order reaction–diffusion, fractional-order diffusion and diffusion–convection. Applications are shown for population dynamics with or without weak Allee effects, speed-limited hyperbolic diffusion, material phase field dynamics, soil–water–plant dynamics and calcium transport on the curved surface of an oocyte. Beyond non-classical symmetry analysis, examples of other conditionally integrable equations are given; nonlinear diffusion in 1 + 2 dimensions and the Madelung–Burgers quantum fluid in 1 + 3 dimensions.
Klebsiella pneumoniae Co-infection Leads to Fatal Pneumonia in SARS-CoV-2-infected Mice
Authors: Villalva Crystal , Patil Girish , Narayanan Sai , Chanda Debarati , Ghimire Roshan , Snider Timothy , Ramachandran Akhilesh , Channappanavar Rudragouda , More Sunil
Published: August 2023

SARS-CoV-2 patients have been reported to have high rates of secondaryKlebsiella pneumoniaeinfections.Klebsiella pneumoniaeis a commensal that is typically found in the respiratory and gastrointestinal tracts. However, it can cause severe disease when a person’s immune system is compromised. Despite a high number ofK. pneumoniaecases reported in SARS-CoV-2 patients, a co-infection animal model evaluating the pathogenesis is not available. We describe a mouse model to study disease pathogenesis of SARS-CoV-2 andK. pneumoniaeco-infection. BALB/cJ mice were inoculated with mouse-adapted SARS-CoV-2 followed by a challenge withK. pneumoniae. Mice were monitored for body weight change, clinical signs, and survival during infection. The bacterial load, viral titers, immune cell accumulation and phenotype, and histopathology were evaluated in the lungs. The co-infected mice showed severe clinical disease and a higher mortality rate within 48 h ofK. pneumoniaeinfection. The co-infected mice had significantly elevated bacterial load in the lungs, however, viral loads were similar between co-infected and single-infected mice. Histopathology of co-infected mice showed severe bronchointerstitial pneumonia with copious intralesional bacteria. Flow cytometry analysis showed significantly higher numbers of neutrophils and macrophages in the lungs. Collectively, our results demonstrated that co-infection of SARS-CoV-2 withK. pneumoniaecauses severe disease with increased mortality in mice.
Targeted Amplification and Genetic Sequencing of the Severe Acute Respiratory Syndrome Coronavirus 2 Surface Glycoprotein
Authors: Keller Matthew W. , Keong Lisa M. , Rambo-Martin Benjamin L. , Hassell Norman , Lacek Kristine , Wilson Malania M. , Kirby Marie K. , Liddell Jimma , Owuor D. Collins , Sheth Mili , Madden Joseph , Lee Justin S. , Kondor Rebecca J. , Wentworth David E. , Barnes John R.
Published: August 2023

The SARS-CoV-2 spike protein is a highly immunogenic and mutable protein that is the target of vaccine prevention and antibody therapeutics. This makes the encoding S-gene an important sequencing target. The SARS-CoV-2 sequencing community overwhelmingly adopted tiling amplicon-based strategies for sequencing the entire genome. As the virus evolved, primer mismatches inevitably led to amplicon drop-out. Given the exposure of the spike protein to host antibodies, mutation occurred here most rapidly, leading to amplicon failure over the most insightful region of the genome. To mitigate this, we developed SpikeSeq, a targeted method to amplify and sequence the S-gene. We evaluated 20 distinct primer designs through iterativein silicoandin vitrotesting to select the optimal primer pairs and run conditions. Once selected, periodicin silicoanalysis monitor primer conservation as SARS-CoV-2 evolves. Despite being designed during the Beta wave, the selected primers remain > 99% conserved through Omicron as of 2023-04-14. To validate the final design, we compared SpikeSeq data and National SARS-CoV-2 Strain Surveillance whole-genome data for 321 matching samples. Consensus sequences for the two methods were highly identical (99.998%) across the S-gene. SpikeSeq can serve as a complement to whole-genome surveillance or be leveraged where only S-gene sequencing is of interest. While SpikeSeq is adaptable to other sequencing platforms, the Nanopore platform validated here is compatible with low to moderate throughputs, and its simplicity better enables users to achieve accurate results, even in low resource settings.
Comparative Analysis of Methods to Reduce Activation Signature Gene Expression in PBMCs
Authors: Andriamboavonjy Lovatiana , MacDonald Adam , Hamilton Laura K. , Labrecque Marjorie , Boivin Marie-Noёlle , Karamchandani Jason , Stratton Jo Anne , Tetreault Martine
Published: August 2023

Preserving thein vivocell transcriptome is essential for accurate profiling, yet factors during cell isolation including timeex vivoand temperature induce artifactual gene expression, particularly in stress-responsive immune cells. In this study, we investigated two methods to mitigateex vivoactivation signature gene (ASG) expression in peripheral blood mononuclear cells (PBMCs): transcription and translation inhibitors (TTis) and cold temperatures during isolation. Comparative analysis of PBMCs isolated with TTis revealed reduced ASG expression. However, TTi treatment impaired responsiveness to LPS stimulation in subsequentin vitroexperiments. In contrast, cold isolation methods also prevented ASG expression; up to a point where the addition of TTis during cold isolation offered minimal additional advantage. These findings highlight the importance of considering the advantages and drawbacks of different isolation methods to ensure accurate interpretation of PBMC transcriptomic profiles.

Highlights

Traditional room temperature isolation methods trigger activation signature gene expression in PBMCs, even when rapidly isolated, whereas 4°C isolation methods do not.

Transcription and translation inhibitors and cold processing techniques reduce activation signature gene expression via shared mechanisms.

PBMCs treated with transcription and translation inhibitors lose responsiveness to external stimuli.

Cold isolation methods offer a suitable and inexpensive alternative to mitigate activation signature gene expression in PBMCs.
Childhood-onset asthma is characterized by airway epithelial hillock-to-squamous differentiation in early life
Authors: Kersten Elin T.G. , Pett J. Patrick , Malmström Kristiina , Chun Yoojin , Jonker Marnix R. , Wilbrey-Clark Anna , Worlock Kaylee B , van den Berge Maarten , Vermeulen Roel C.H. , Vonk Judith M. , Sebire Neil , Lohi Jouko , Timens Wim , Teichmann Sarah A , Bunyavanich Supinda , Nikolić Marko Z. , Nawijn Martijn C. , Mäkelä Mika J. , Meyer Kerstin B. , Koppelman Gerard H.
Published: August 2023

Childhood-onset asthma is characterized by Type 2-inflammation and airway wall remodeling, but mechanisms of asthma development in the first years of life remain unclear. Here, we investigate transcriptional changes in airway wall biopsies of 22 symptomatic one year old children and relate these to asthma at school age. We demonstrate that pre-asthmatic children (n = 10) overexpressed a gene signature characteristic for an airway epithelial differentiation trajectory via hillock cells towards squamous cells (adjusted p-value 8.06e-16), whilst there was no association with gene signatures of Type 2-inflammation or eosinophil activation. Genes expressed along this trajectory are linked to an altered epithelial barrier function, innate immune activation and extracellular matrix remodeling. Functional GWAS analysis supports a causal link between childhood-onset, but not adult-onset asthma, and the hillock-squamous cell differentiation trajectory. Next, we confirmed the presence of hillock-like cells at the RNA and protein level in pediatric upper and lower airway samples. These findings identify a novel mechanism by which an aberrant airway epithelial differentiation trajectory may contribute to a pre-asthmatic state, highlighting the difference between the early origins of childhood-onset asthma and adult asthma, and point to possible new targets for the early diagnosis and treatment of asthma in the first two years of life.

One Sentence Summary

RNA sequencing in bronchial biopsies from wheezing infants and children < 2 years shows evidence for an airway epithelial hillock-to-squamous differentiation pathway that marks the development of asthma.
Evolution of alternative reproductive systems inBacillusstick insects
Authors: Lavanchy Guillaume , Brandt Alexander , Bastardot Marc , Dumas Zoe , Labedan Marjorie , Massy Morgane , Toubiana William , TranVan Patrick , Luchetti Andrea , Scali Valerio , Mantovani Barbara , Schwander Tanja
Published: August 2023

Reproduction is a key feature of all organisms, yet the way in which it is achieved varies greatly across the tree of life. One striking example of this variation is the stick insect genusBacillus, in which five different reproductive modes have been described: sex, facultative and obligate parthenogenesis, and two highly unusual reproductive modes: hybridogenesis and androgenesis. Under hybridogenesis, the entire genome from the paternal species is eliminated, and replaced each generation by mating with the corresponding species. Under androgenesis, an egg is fertilized but the developing diploid offspring bear two paternal genomes, and no maternal genome, as a consequence of unknown mechanisms. Here, we re-evaluate previous descriptions ofBacilluslineages and the proposed F1hybrid ancestries of the hybridogenetic and obligately parthenogenetic lineages (based on allozymes and karyotypes) from Sicily, where all these reproductive modes are found. We generate a chromosome-level genome assembly for a facultative parthenogenetic species (B. rossius) and combine extensive field sampling with RADseq and mtDNA data. We identify and genetically corroborate all previously described species and confirm the ancestry of hybrid lineages. All hybrid lineages have fully retained their F1 hybrid constitution throughout the genome, indicating that the elimination of the paternal genome in hybridogens is always complete and that obligate parthenogenesis inBacillushybrid species is not associated with an erosion of heterozygosity as known in other hybrid asexuals. Our results provide a stepping stone towards understanding the transitions between reproductive modes and the proximate mechanisms of genome elimination.
Multiscale Rheology of Aging Cancer Spheroids
Authors: Gnanachandran Kajangi , Berardi Massimiliano , Skar Asmus , Pyka-Fościak Grażyna , Pabijan Joanna , Alonso Javier Lopez , Akca B. Imran , Lekka Małgorzata
Published: August 2023

Cancer spheroids offer a valuable experimental model that mimics the complexity and heterogeneity of solid tumors. Characterizing their mechanical response is crucial for understanding tumor development, progression, and drug response. Currently, whole live spheroids are analyzed primarily using image analysis, which is challenging, requires extended incubation times, and has limited imaging depth. Here, we present a new label-free approach for characterizing sub-superficial structures of bladder cancer spheroids and measuring their mechanical response at three distinct stages of cancer progression. We study the microrheological changes induced by aging at the cellular and cluster levels by conducting a multi-physics characterization and modeling approach. We find that spheroids exhibit viscoelastic behavior that can be described by fractional models. We show that spheroids are mechanically heterogeneous, with strong depth and time-dependent variations associated with evolving structural features. Our approach opens new possibilities to study 3Din vitromodels, paving the way for the discovery of novel and more precise procedure in cancer diagnosis based on the use of mechanomarkers.
High-intensity physiological activation disrupts the neural signatures of conflict processing
Authors: Avancini Chiara , Ciria Luis F. , Alameda Clara , Palenciano Ana Francisca , Canales-Johnson Andrés , Bekinschtein Tristan , Sanabria Daniel
Published: August 2023

Physical activation fluctuates throughout the day. Previous studies have shown that during periods of reduced activation, cognitive control remains resilient due to neural compensatory mechanisms. In this study, we in-vestigated the effects of high physical activation on both behavioural and neural markers of cognitive control. We hypothesized that while behavioural measures of cognitive control would remain intact during periods of high activation, there would be observable changes in neural correlates. In our electroencephalography study, we manipulated levels of physical activation through physical exercise. Although we observed no significant impact on behavioural measures of cognitive conflict, both univariate and multivariate time-frequency markers proved unreliable under conditions of high activation. Moreover, there was no modulation of whole-brain connectivity measures by physical activation. We suggest that this dissociation between behavioural and neural measures indicates that the human cognitive control system remains resilient even at high activation, possibly due to underlying neural compensatory mechanisms.
Clearwing butterflies challenge the thermal melanism hypothesis
Authors: Ossola Violaine , Pottier Fabien , Pinna Charline , Bougiouri Katia , Tournié Aurélie , Michelin Anne , Andraud Christine , Gomez Doris , Elias Marianne
Published: August 2023

In contrast to most butterflies harboring opaque wing colorations, some species display large transparent patches on their wings. Wing transparency, which entails a dramatic reduction of pigmentation, raises the question of potential costs for vital functions, such as thermoregulation, especially along climatic gradients. The thermal melanism hypothesis posits that darker colorations should be favored in colder environments, which enables them to absorb more radiation and maintain a body temperature compatible with activity. This prediction extends to the near infrared (NIR) range, which represents a large proportion of solar radiation. Here we assess the implications of wing transparency for light absorption and thermal properties in 42 butterfly species from the neotropical tribe Ithomiini that range the extent of transparency, from fully opaque to highly transparent, and we test whether those species conform to the prediction of the thermal melanism hypothesis. We find that transparent wings are less efficient than opaque wings to absorb light across UV, Visible and NIR wavelength ranges, and are also less efficient to collect heat. Moreover, dark coloration occupies a lower proportion of wing area as altitude increases, and ithomiine species harbor more transparency at higher altitudes, where climatic conditions are colder, going strongly against the prediction of the thermal melanism hypothesis. We discuss these surprising results in light of recent studies suggesting that factors other than adaptation to cold, such as predation pressure, physiology or behavior, may have driven the evolution of wing patterns in Ithomiini.

Significance Statement

The thermal melanism hypothesis predicts that organisms should be darker and absorb solar radiation more efficiently in colder environments. The Neotropical butterflies Ithomiini are unusual in that many species harbor large transparent patches on their wings, raising questions related to their efficacy of solar radiation absorption and heating capacities. We investigate optical and thermal properties of several ithomiine species along a climatic gradient. We find that transparent wings are less efficient at absorbing radiation and collecting heat. Unexpectedly, the proportion of transparent species increases with altitude, challenging the thermal melanism hypothesis and suggesting that factors other than adaptation to cold, such as predation pressure, may have driven the evolution of wing patterns in Ithomiini.
Mechanical forces control the valency of the malaria adhesin VAR2CSA by exposing cryptic glycan binding sites
Authors: Roessner Rita , Michelarakis Nicholas , Gräter Frauke , Aponte-Santamaría Camilo
Published: August 2023

Plasmodium falciparum (Pf) is responsible for the most lethal form of malaria. VAR2CSA is an adhesin protein expressed by this parasite at the membrane of infected erythrocytes for attachment on the placenta, leading to pregnancy-associated malaria. VAR2CSA is a large 355 kDa multidomain protein composed of nine extracellular domains, a transmembrane helix, and an intracellular domain. VAR2CSA binds to Chondroitin Sulphate A (CSA) of the proteoglycan matrix of the placenta. Shear flow, as the one occurring in blood, has been shown to enhance the (VAR2CSA-mediated) adhesion ofPf-infected erythrocytes on the CSA-matrix. However, the underlying molecular mechanism governing this enhancement has remained elusive. Here, we address this question by using equilibrium, force-probe, and docking-based molecular dynamics simulations. We subjected the VAR2CSA protein–CSA sugar complex to a force mimicking the elongational tension exerted on this system due to the shear of the flowing blood. We show that upon this force exertion, VAR2CSA undergoes a large opening conformational transition before the CSA sugar chain dissociates from its main binding site. This preferential order of events is caused by the orientation of the molecule during elongation as well as the strong electrostatic attraction of the sugar to the main protein binding site. Upon opening, two additional cryptic CSA binding sites get exposed and a functional dodecameric CSA molecule can be stably accommodated at these force-exposed positions. Thus, our results suggest that mechanical forces, increase the avidity of VAR2CSA, by turning it from a monovalent to a multivalent state. We propose this to be the molecular cause of the observed shear-enhanced adherence. Mechanical control of the valency of VAR2CSA is an intriguing hypothesis that can be tested experimentally and which is of relevance for the understanding of the malaria infection and for the development of anti placental-malaria vaccines targeting VAR2CSA.
Jointly modeling deep mutational scans identifies shifted mutational effects among SARS-CoV-2 spike homologs
Authors: Haddox Hugh K. , Galloway Jared G. , Dadonaite Bernadeta , Bloom Jesse D. , Matsen Frederick A. , DeWitt William S.
Published: August 2023

Deep mutational scanning (DMS) is a high-throughput experimental technique that measures the effects of thousands of mutations to a protein. These experiments can be performed on multiple homologs of a protein or on the same protein selected under multiple conditions. It is often of biological interest to identify mutations with shifted effects across homologs or conditions. However, it is challenging to determine if observed shifts arise from biological signal or experimental noise. Here, we describe a method for jointly inferring mutational effects across multiple DMS experiments while also identifying mutations that have shifted in their effects among experiments. A key aspect of our method is to regularize the inferred shifts, so that they are nonzero only when strongly supported by the data. We apply this method to DMS experiments that measure how mutations to spike proteins from SARS-CoV-2 variants (Delta, Omicron BA.1, and Omicron BA.2) affect cell entry. Most mutational effects are conserved between these spike homologs, but a fraction have markedly shifted. We experimentally validate a subset of the mutations inferred to have shifted effects, and confirm differences of >1,000-fold in the impact of the same mutation on spike-mediated viral infection across spikes from different SARS-CoV-2 variants. Overall, our work establishes a general approach for comparing sets of DMS experiments to identify biologically important shifts in mutational effects.

Significance Statement

Amino-acid mutations to a protein have effects that can shift as the protein evolves or is put under new selective pressure. The effects of amino-acid mutations to a specific protein under a defined selective pressure can be measured by deep mutational scanning experiments. Here, we devise an approach to quantify shifts in mutational effects between experiments performed on different homologs (i.e. variants) of the same protein, or on the same protein selected under different conditions. We use this approach to compare experiments performed on three homologs of SARS-CoV-2 spike, identifying mutations that have shifted in their effect on spike-mediated viral infection by >1,000 fold across SARS-CoV-2 variants.
A Framework for Fast, Large-scale, Semi-Automatic Inference of Animal Behavior from Monocular Videos
Authors: Price Eric , Khandelwal Pranav C. , Rubenstein Daniel I. , Ahmad Aamir
Published: August 2023

An automatic, quick, accurate, and scalable method for animal behavior inference using only videos of animals offers unprecedented opportunities to understand complex biological phenomena and answer challenging ecological questions. The advent of sophisticated machine learning techniques now allows the development and implementation of such a method. However, apart from developing a network model that infers animal behavior from video inputs, the key challenge is to obtain sufficient labeled (annotated) data to successfully train that network - a laborious task that needs to be repeated for every species and/or animal system. Here, we propose solutions for both problems, i) a novel methodology for rapidly generating large amounts of annotated data of animals from videos and ii) using it to reliably train deep neural network models to infer the different behavioral states of every animal in each frame of the video. Our method’s workflow is bootstrapped with a relatively small amount of manually-labeled video frames. We develop and implement this novel method by building upon the open-source tool Smarter-LabelMe, leveraging deep convolutional visual detection and tracking in combination with our behavior inference model to quickly produce large amounts of reliable training data. We demonstrate the effectiveness of our method on aerial videos of plains and Grévy’s Zebras (Equus quaggaandEquus grevyi). We fully open-source the code1of our method as well as provide large amounts of accurately-annotated video datasets2of zebra behavior using our method. A video abstract of this paper is available here3.
Modeling individual variability in habitat selection and movement using integrated step-selection analyses
Authors: Chatterjee Nilanjan , Wolfson David , Kim Dongmin , Velez Juliana , Freeman Smith , Bacheler Nathan M. , Shertzer Kyle , Taylor J. Christopher , Fieberg John
Published: August 2023

1. Integrated step-selection analyses(ISSAs) are frequently used to study habitat selection using animal movement data. Methods for incorporating random effects in ISSAs have been developed, making it possible to quantify variability among animals in their space-use patterns. Although it is possible to model variability in both habitat selection and movement parameters, applications to date have focused on the former despite the widely acknowledged and important role that movement plays in determining ecological processes from the individual to ecosystem level. One potential explanation for this omission is the absence of readily-available software or examples demonstrating methods for estimating movement parameters in ISSAs with random effects.

2. We demonstrated methods for characterizing among-individual variability in both movement and habitat-selection parameters using a simulated data set and by fitting two models to an acoustic telemetry data set containing locations of 35 red snapper (Lutjanus campechanus). Movement kernels were assumed to depend on either the type of benthic reef habitat in which the fish was located (model 1) or the distance between the fish’s current location and nearest edge habitat (model 2). In both models, we also quantified habitat selection for different benthic habitat classes and distance to edge habitat, and we allowed for individual variability in movement and habitat-selection parameters using random effects.

3. The simulation example highlights the benefits of a mixed effects specification, namely we can increase precision when estimating individual-specific movement parameters by borrowing information across like individuals. In our applied example, we found substantial among-individual variability in both habitat selection and movement parameters. Nonetheless, most red snapper selected for hardbottom habitat and for locations nearer to edge habitat. They also moved less when in hardbottom habitat. Turn angles were frequently near ±π, but were more dispersed when fish were far away from edge habitat.

4. We provide code templates and functions for quantifying variability in movement and habitat-selection parameters when implementing ISSAs with random effects. In doing so, we hope to encourage ecologists conducting ISSAs to take full advantage of their ability to model among-individual variability in both habitat-selection and movement patterns.
How do Cicadas Emerge Together? Thermophysical Aspects of Their Collective Decision-Making
Authors: Goldstein Raymond E. , Jack Robert L. , Pesci Adriana I.
Published: August 2023

Certain periodical cicadas exhibit life cycles with durations of 13 or 17 years, and it is now generally accepted that such large prime numbers arise evolutionarily to avoid synchrony with predators. Less well explored is the question ofhow, in the face of intrinsic biological and environmental noise, insects within a brood emerge together in large successive swarms from underground during springtime warming. Here we consider the decision-making process of underground cicada nymphs experiencing random but spatially-correlated thermal microclimates like those in nature. Introducing short-range communication between insects leads to a model of consensus building that maps on to the statistical physics of an Ising model with a quenched, spatially correlated random magnetic field and annealed site dilution, which displays the kinds of collective swarms seen in nature.
Autoinhibition in the Signal Transducer CIN85 Modulates B Cell Activation
Authors: Sieme Daniel , Engelke Michael , Rezaei-Ghaleh Nasrollah , Becker Stefan , Wienands Jürgen , Griesinger Christian
Published: August 2023

Signal transduction by the ligated B cell antigen receptor (BCR) depends on the pre-organization of its intracellular components, such as the effector proteins SLP65 and CIN85 within phase-separated condensates. These liquid-like condensates are based on the interaction between three Src homology 3 (SH3) domains and corresponding proline-rich recognition motifs (PRM) in CIN85 and SLP65, respectively. However, detailed information on the protein conformation and how it impacts on the capability of SLP65/CIN85 condensates to orchestrate BCR signal transduction is still lacking. This study identifies a hitherto unknown intramolecular SH3:PRM interaction between the C-terminal SH3 domain (SH3C) of CIN85 and an adjacent PRM. We used high-resolution nuclear magnetic resonance (NMR) experiments to study the flexible linker region containing the PRM and determined the extent of the interaction in multidomain constructs of the protein. Moreover, we observed that the phosphorylation of a serine residue located in the immediate vicinity of the PRM regulates this intramolecular interaction. This allows for a dynamic modulation of CIN85’s valency towards SLP65, regulating the extent of liquid-liquid phase separation. B cell culture experiments further revealed that the PRM/SH3C interaction is crucial for maintaining the physiological level of SLP65/CIN85 condensate formation, activation-induced membrane recruitment of CIN85, and subsequent mobilization of Ca2+. Our findings therefore suggest that the intramolecular interaction to the adjacent disordered linker is effective in modulating CIN85’s valency bothin vitroandin vivo. This therefore constitutes a powerful way for the modulation of SLP65/CIN85 condensate formation and subsequent B cell signaling processes within the cell.
Reactivation strength during cued recall is modulated by graph distance within cognitive maps
Authors: Kern Simon , Nagel Juliane , Gerchen Martin F , Gürsoy Çağatay , Meyer-Lindenberg Andreas , Kirsch Peter , Dolan Raymond J , Gais Steffen , Feld Gordon B
Published: August 2023

Declarative memory retrieval is thought to involve reinstatement of neuronal activity patterns elicited and encoded during a prior learning episode. Furthermore, it is suggested that two mechanisms operate during reinstatement, dependent on task demands: individual memory items can be reactivated simultaneously as a clustered occurrence or, alternatively, replayed sequentially as temporally separate instances. In the current study, participants learned associations between images that were embedded in a directed graph network and retained this information over a brief 8-minute consolidation period. During a subsequent cued recall session, participants retrieved the learned information while undergoing magnetoencephalographic (MEG) recording. Using a trained stimulus decoder, we found evidence for clustered reactivation of learned material. Reactivation strength of individual items during clustered reactivation decreased as a function of increasing graph distance, an ordering present solely for successful retrieval but not for retrieval failure. In line with previous research, we found evidence that sequential replay was dependent on retrieval performance and was most evident in low performers. The results provide evidence for distinct performance-dependent retrieval mechanisms with graded clustered reactivation emerging as a plausible mechanism to search within abstract cognitive maps.
Sea butterflies in a pickle: Reliable biomarkers and seasonal sensitivity of pteropods to ocean acidification in the Gulf of Maine
Authors: Maas Amy E. , Lawson Gareth L. , Bergan Alexander J. , Wang Zhaohui Aleck , Tarrant Ann M.
Published: August 2023

The passive dissolution of anthropogenically produced CO2into the ocean system is reducing ocean pH and changing a suite of chemical equilibria, with negative consequences for some marine organisms, in particular those that bear calcium carbonate shells. Although our monitoring of these chemical changes has improved, we have not developed effective tools to translate observations, which are typically of the pH and carbonate saturation state, into ecologically relevant predictions of biological risks. One potential solution is to develop bioindicators: biological variables with a clear relationship to environmental risk factors that can be used for assessment and management. Thecosomatous pteropods, a group of pelagic shelled marine gastropods, whose biological responses to CO2have been suggested as potential bioindicators of OA owing to their sensitivity to acidification in both laboratory and the natural environment. Using five CO2exposure experiments, occurring across 4 seasons and running for up to 15 days, we describe a consistent relationship between saturation state, shell transparency, and duration of exposure, as well as identify a suite of genes that could be used for biological monitoring. We clarify variations in thecosome responses due to seasonality, resolving prior uncertainties and demonstrating the range of their phenotypic plasticity. These biomarkers of acidification stress can be implemented into ecosystem models and monitoring programs in regions where pteropods are found, while the approach will serve as an example for other regions on how to bridge the gap between point-based chemical monitoring and biologically relevant assessments of ecosystem health.

Summary Statement

Despite seasonal variability, pteropods exposed to acidification over multiple seasons reveal consistent patterns in gene expression and shell condition that can be used as bioindicators of ocean acidification stress.
NetActivity enhances transcriptional signals by combining gene expression into robust gene set activity scores through interpretable autoencoders
Authors: Ruiz-Arenas Carlos , Marín-Goñi Irene , Wang Liewei , Ochoa Idoia , Pérez-Jurado Luis A , Hernaez Mikel
Published: August 2023

Grouping gene expression into gene set activity scores (GSAS) provides better biological insights than studying individual genes. However, existing gene set projection methods cannot return representative, robust, and interpretable GSAS. We developedNetActivity, a framework based on a sparsely-connected autoencoder and a three-tier training that yields robust and interpretable GSAS.NetActivitywas trained with 1,518 well-known gene sets and all GTEx samples, returning GSAS representative of the original transcriptome and assigning higher importance to more biologically relevant genes. Moreover,NetActivityreturns GSAS with a more consistent definition than GSVA and hipathia, state-of-the-art gene set projection methods. Finally,NetActivityenables combining bulk RNA-seq and microarray datasets in a meta-analysis of prostate cancer progression, highlighting gene sets related to cell division. When applied to metastatic prostate cancer, gene sets associated with cancer progression were also altered due to drug resistance, while a classical enrichment analysis identified gene sets irrelevant to the phenotype.
Mitochondrial Ca2+uniporter (MCU) variants form plasma-membrane channels
Authors: Polina Iuliia , Mishra Jyotsna , Cypress Michael W , Landherr Maria , Valkov Nedyalka , Chaput Isabel , Nieto Bridget , Mende Ulrike , Zhang Peng , Jhun Bong Sook , O-Uchi Jin
Published: August 2023

MCU is widely recognized as a responsible gene for encoding a pore-forming subunit of highly mitochondrial-specific and Ca2+-selective channel, mitochondrial Ca2+uniporter complex (mtCUC). Here, we report a novel short variant derived from the MCU gene (termed MCU-S) which lacks mitochondria-targeted sequence and forms a Ca2+- permeable channel outside of mitochondria. MCU-S was ubiquitously expressed in all cell-types/tissues, with particularly high expression in human platelets. MCU-S formed Ca2+channels at the plasma membrane, which exhibited similar channel properties to those observed in mtCUC. MCU-S channels at the plasma membrane served as an additional Ca2+influx pathway for platelet activation. Our finding is completely distinct from the originally reported MCU gene function and provides novel insights into the molecular basis of MCU variant-dependent cellular Ca2+handling.
The axes of biology: a novel axes-based network embedding paradigm to decipher the functional mechanisms of the cell
Authors: Doria-Belenguer Sergio , Xenos Alexandros , Ceddia Gaia , Malod-Dognin Noël , Pržulj Nataša
Published: August 2023

Common approaches for deciphering biological networks involve network embedding algorithms. These approaches strictly focus on clustering the genes’ embedding vectors and interpreting such clusters to reveal the hidden information of the networks. However, the difficulty in interpreting the genes’ clusters and the limitations of the functional annotations’ resources hinder the identification of the currently unknown cell’s functioning mechanisms. Thus, we propose a new approach that shifts this functional exploration from the embedding vectors of genes in space to the axes of the space itself. Our methodology better disentangles biological information from the embedding space than the classic gene-centric approach. Moreover, it uncovers new data-driven functional interactions that are unregistered in the functional ontologies, but biologically coherent. Furthermore, we exploit these interactions to define new higher-level annotations that we term Axes-Specific Functional Annotations and validate them through literature curation. Finally, we leverage our methodology to discover evolutionary connections between cellular functions and the evolution of species.
Local population structure in Cambridgeshire during the Roman occupation
Authors: Scheib Christiana L. , Hui Ruoyun , Rose Alice K. , Solnik Anu , D’Atanasio Eugenia , Inskip Sarah A. , Cessford Craig , Griffith Samuel J. , Wiseman Rob , Neil Benjamin , Biers Trish , Harknett Sarah-Jane , Sasso Stefania , Biagini Simone A. , Runfeldt Göran , Duhig Corinne , Evans Christopher , O’Connell Tamsin C. , Metspalu Mait , Millett Martin J. , Robb John E. , Kivisild Toomas
Published: August 2023

The Roman period saw the empire expand across Europe and the Mediterranean, including much of what is today the United Kingdom. While there is written evidence of high mobility into and out of Britain for administrators, traders and the military, the impact of imperialism on local population structure is invisible in the textual record. The extent of genetic change that occurred in Britain before the Early Medieval Period and how closely linked by genetic kinship the local populations were, remains underexplored. Here, using genome-wide data from 52 ancient individuals from Cambridgeshire, we show low levels of genetic ancestry differentiation between Romano-British sites and lower levels of runs of homozygosity over 4 centimorgans (cM than in the Bronze Age and Neolithic. We find fourteen cases of genetic relatedness within and one between sites without evidence of patrilineal dominance and one case of temporary mobility within a family unit during the Late Romano-British period. We also show that the modern patterns of genetic ancestry composition in Modern Britain emerged after the Roman period.
Thinner is not always better: Optimising cryo lamellae for subtomogram averaging
Authors: Tuijtel Maarten W. , Kreysing Jan Philipp , Welsch Sonja , Hummer Gerhard , Beck Martin , Turoňová Beata
Published: August 2023

Cryo-electron tomography (cryo-ET) is a powerful method to elucidate subcellular architecture and to structurally analyse biomoleculesin situby subtomogram averaging (STA). Specimen thickness is a key factor affecting cryo-ET data quality. Cells that are too thick for transmission imaging can be thinned by cryo-focused-ion-beam (cryo-FIB) milling. However, optimal specimen thickness for cryo-ET on lamellae has not been systematically investigated. Furthermore, the ions used to ablate material can cause damage in the lamellae, thereby reducing STA resolution. Here, we systematically benchmark the resolution depending on lamella thickness and the depth of the particles within the sample. Up to ca. 180 nm, lamella thickness does not negatively impact resolution. This shows that there is no need to generate very thin lamellae and thickness can be chosen such that it captures major cellular features. Furthermore, we show that gallium-ion-induced damage extends to depths of up to 30 nm from either lamella surface.
Phenotypic Plasticity Drives Seasonal Thermal Tolerance in a Baltic Copepod
Authors: Hahn Alexandra , Brennan Reid S.
Published: August 2023

Seasonal changes in environmental conditions require substantial physiological responses for population persistence. Phenotypic plasticity is a common mechanism to tolerate these changes, but for organisms with short generation times rapid adaptation may also be a contributing factor. Here, we aimed to disentangle the impacts of adaptation from phenotypic plasticity on thermal tolerance of the calanoid copepod Acartia hudsonica collected throughout spring and summer of a single year. We used a common garden (11 C and 18 C) design to determine the relative impacts of plasticity versus adaptation. Acartia hudsonica were collected from five time points across the season and thermal tolerance was determined using critical thermal maximum CTmax followed by additional measurements after one generation of common garden. As sea surface temperature increased through the season, field collected individuals showed corresponding increases in thermal tolerance but decreases in body size. Despite different thermal tolerances of wild collections, common garden animals did not differ in CTmax within thermal treatments. Instead, there was evidence of phenotypic plasticity where higher temperatures were tolerated by the 18 C versus the 11 C treatment animals across all collections. Acclimation also had significant effects on body size, with higher temperatures resulting in smaller individuals, consistent with the temperature size rule. Therefore, the differences in thermal tolerance and body size observed in field collected A. hudsonica were likely driven by plasticity rather than adaptation. However, the observed decrease in body size suggests that nutrient availability and ecosystem functioning could be impacted if temperatures consistently increase with no change in copepod abundance. This is the first record of A. hudsonica in the Baltic Sea known to the authors.
Dynamic proximity interaction profiling suggests that YPEL2 is involved in cellular stress surveillance
Authors: Turan Gizem , Olgun Çağla Ece , Ayten Hazal , Toker Pelin , Ashyralyyev Annageldi , Savaş Büşra , Karaca Ezgi , Muyan Mesut
Published: August 2023

YPEL2 is a member of the evolutionarily conserved YPEL family involved in cellular proliferation, mobility, differentiation as well as senescence and death. However, the mechanism by which YPEL2, or YPEL proteins, mediates its effects is yet unknown. Proteins perform their functions in a network of proteins whose identities, amounts, and compositions change spatiotemporally in a lineage-specific manner in response to internal and external stimuli. We here explored interaction partners of YPEL2 by using dynamic TurboID-coupled mass spectrometry analyses to infer a function for the protein. Our results using inducible transgene expressions in COS7 cells indicate that proximity interaction partners of YPEL2 are largely involved in RNA and mRNA metabolic processes, ribonucleoprotein complex biogenesis, regulation of gene silencing by miRNA, and cellular responses to stress. We showed that YPEL2 interacts with RNA binding protein ELAVL1 and selective autophagy receptor SQSTM1. We also found that YPEL2 participates in events associated with the formation/disassembly of stress granules in response to sodium arsenite an oxidative stress inducer. Establishing a point of departure in the delineation of structural/functional features of YPEL2, our results suggest that YPEL2 may be involved in stress surveillance mechanisms.
Hidden in plain sight: the invasive macroalgaCaulerpa proliferaevades detection by environmental DNA methods due to negligible shedding
Authors: Waters Tanner , Langlois Kylie , Gold Zack , Theroux Susanna , Eagle Robert A.
Published: August 2023

The macroalgaeCaulerpa proliferais considered an invasive species in many environments and can colonize large patches of seafloor, reduce native species, and alter ecosystem functioning. Environmental managers need a rapid and cost-effective monitoring tool for tracking the spread of this invasive species. We developed a digital PCR assay for detection ofC. proliferafrom environmental DNA seawater samples. We demonstrate, in both field and laboratory experiments, that the invasive algaeC. proliferais undetectable in practical applications of eDNA due to its minimal shedding. To test why, we conducted tank-based shedding experiments for two California invasive algae species,C. proliferaandSargassum horneri. Copy numbers ofC. proliferaeDNA detected in the experimental tanks were found to be two orders of magnitude lower thanS. horneri. A meta-analysis of steady state eDNA produced by aquatic organisms reported in the literature showC. proliferato have the lowest recorded steady state concentrations of eDNA in the water column. We attributeC. proliferalow eDNA shedding to its unique biology as a unicellular, multinucleate, macroscopic siphonous algae which reduces the possible modes of eDNA release compared to multicellular organisms. Our results highlight the value of benchmarking and validating eDNA surveys in both field and laboratory settings and potential limits of eDNA approaches for some applications. These results also emphasize the importance of organismal physiology in eDNA shedding rates, variations in mechanisms of eDNA shedding between organisms, and characterizing shedding rates for accurate interpretation of eDNA results.
DePARylation is critical for S phase progression and cell survival
Authors: Nie Litong , Wang Chao , Huang Min , Liu Xiaoguang , Feng Xu , Tang Mengfan , Li Siting , Hang Qinglei , Teng Hongqi , Shen Xi , Ma Li , Gan Boyi , Chen Junjie
Published: August 2023

Poly(ADP-ribose)ylation or PARylation by PAR polymerase 1 (PARP1) and dePARylation by poly(ADP-ribose) glycohydrolase (PARG) are equally important for the dynamic regulation of DNA damage response. PARG, the most active dePARylation enzyme, is recruited to sites of DNA damage via pADPr-dependent and PCNA-dependent mechanisms. Targeting dePARylation is considered an alternative strategy to overcome PARP inhibitor resistance. However, precisely how dePARylation functions in normal unperturbed cells remains elusive. To address this challenge, we conducted multiple CRISPR screens and revealed that dePARylation of S phase pADPr by PARG is essential for cell viability. Loss of dePARylation activity initially induced S phase-specific pADPr signaling, which resulted from unligated Okazaki fragments and eventually led to uncontrolled pADPr accumulation and PARP1/2-dependent cytotoxicity. Moreover, we demonstrated that proteins involved in Okazaki fragment ligation and/or base excision repair regulate pADPr signaling and cell death induced by PARG inhibition. In addition, we determined that PARG expression is critical for cellular sensitivity to PARG inhibition. Additionally, we revealed that PARG is essential for cell survival by suppressing pADPr. Collectively, our data not only identify an essential role for PARG in normal proliferating cells but also provide a potential biomarker for the further development of PARG inhibitors in cancer therapy.