bluuebunny/crossref_metadata_2025 huggingface dataset:
A Phenome-wide association study of genetically determined nicotine metabolism reveals novel links with health-related outcomes
Authors: Buchwald Jadwiga , Lehtimäki Terho , Raitakari Olli , Salomaa Veikko , Kaprio Jaakko , Pirinen Matti
Published: December 2023

Background

Faster nicotine metabolism, defined as the nicotine metabolite ratio (NMR), is known to associate with heavier smoking and challenges in smoking cessation. However, the broader health implications of genetically determined nicotine metabolism are not well characterized.

Methods

We performed a hypothesis-free phenome-wide association study (PheWAS) of over 21,000 outcome variables from UK Biobank (UKB) to explore how the NMR (measured as the 3-hydroxycotinine-to-cotinine ratio) associates with the phenome. As the exposure variable, we used a genetic score for faster nicotine metabolism based on 10 putative causal genetic variants, explaining 33.8 % of the variance in the NMR. We analysed ever and never smokers separately to assess whether a causal pathway through nicotine metabolism is plausible.

Results

A total of 57 outcome variables reached phenome-wide significance at a false discovery rate of 5 %. We observed expected associations with several phenotypes related to smoking and nicotine, but could not replicate prior findings on cessation. Importantly, we found novel associations between genetically determined faster nicotine metabolism and adverse health outcomes, including unfavourable liver enzyme and lipid values, as well as increased caffeine consumption. These associations did not appear to differ between ever and never smokers, suggesting the corresponding pathways may not involve nicotine metabolism. No favourable health outcomes were linked to genetically determined faster nicotine metabolism.

Conclusions

Our findings support a possibility that a future smoking cessation therapy converting fast metabolizers of nicotine to slower ones could work without adverse side effects and potentially even provide other health-related benefits.
The effect of leisure activities on quality-of-life scores for children with complex needs: A service evaluation in Wales, UK
Authors: McGrath Nicole , Astill Fiona , Collins Bethan , Maguire Sabine , Kemp Alison , Hurt Lisa
Published: December 2023

Purpose

Recent guidance has resulted in an increased level of interest in the wellbeing of children and young people, including those with complex needs. Evaluation of quality of life in this population is notoriously difficult, but has become increasingly vital when assessing the value of a service.

Methods

A previously validated tool, Quality of life Inventory-Disability (QI-Disability), was used in conjunction with parental reports on quality-of-life measures for children and young people before and after 6 and 12 months of attending specialist leisure activities provided by a charity (Sparkle) at children’s centres in South Wales.

Results

QI-Disability scores improved overall after 6 and 12 months of attending Sparkle club activities. However, the only statistically significant improvement was in the QI-Disability positive emotions domain. Parental reports also confirmed that children and young people were making progress towards their personal goals.

Conclusion

Collecting evaluation data within real-world services is challenging but essential. This paper uses quality-of-life measures to demonstrate how leisure activities provided by Sparkle improve scores for children with disabilities, including evidence of the perceived value for children, young people and parents.

Plain English summary

There is little previous research evaluating specialist leisure activities provided for children and young people with disabilities within real-world services. This evaluation aimed to find out if specialist leisure activities improved wellbeing scores for children with complex needs. We used parent-report questionnaires to measure changes to children’s quality of life whilst accessing these leisure activities. We found there is a benefit to children and young people with complex needs and their families when they participate in specialist leisure activities, and children experienced more positive emotions after accessing for 6 months.
Antibodies toAedes aegyptiD7L salivary proteins as a new serological tool to estimate human exposure toAedesmosquitoes
Authors: Chea Sophana , Willen Laura , Nhek Sreynik , Ly Piseth , Tang Kristina , Oristian James , Salas-Carrillo Roberto , Ponce Aiyana , Leon Paola Carolina Valenzuela , Kong Dara , Ly Sokna , Sath Ratanak , Lon Chanthap , Leang Rithea , Huy Rekol , Yek Christina , Valenzuela Jesus G. , Calvo Eric , Manning Jessica E. , Oliveira Fabiano
Published: December 2023

1

Introduction

Aedes spp.are the most prolific mosquito vectors in the world. Found on every continent, they can effectively transmit various arboviruses, including the dengue virus which continues to cause outbreaks worldwide and is spreading into previously non-endemic areas. The lack of widely available dengue vaccines accentuates the importance of targeted vector control strategies to reduce the dengue burden. High-throughput sensitive tools to estimate human-mosquito contact and evaluate vector control interventions are lacking. We propose a novel serological tool that allows rapid screening of large human cohorts for exposure to potentially infectious mosquitoes and effective targeting of vector control.

Methods

We tested 563 serum samples from a longitudinal pediatric cohort study previously conducted in Cambodia. Children enrolled in the study were dengue-naïve at baseline and were followed biannually for dengue incidence for two years. We used Western blotting and enzyme-linked immunosorbent assays to identify the most immunogenicAedes aegyptisalivary proteins and measure total anti-Ae. AegyptiIgG.

Results

We found a strong correlation (rs=0.86) between the combined IgG responses against AeD7L1 and AeD7L2 recombinant proteins and those to whole salivary gland homogenate. We observed seasonal fluctuations of AeD7L1+2 IgG responses, corresponding toAedes spp.abundance in the region, and no cross-reactivity withCulex quinquefasciatusandAnopheles dirusmosquitoes. The baseline median AeD7L1+2 IgG responses for young children were higher in those who developed asymptomatic dengue versus those who developed symptomatic dengue.

Conclusion

The IgG response against AeD7L1+2 recombinant proteins is a highly sensitive andAedesspecific marker of human exposure toAedesbites that can facilitate standardization of future serosurveys and epidemiological studies by its ability to provide a robust estimation of human-mosquito contact in a high-throughput fashion.
Connectivity at home: A data-driven connectivity modeling framework for home range movements in heterogeneous landscapes
Authors: Merkens Lisa , Mimet Anne , Bae Soyeon , Fairbairn Andrew , Mühlbauer Maximilian , Lauppe Elio , Mesarek Florian , Stauffer-Bescher Daniel , Hauck Thomas E. , Weisser Wolfgang W.
Published: December 2023

Landscape connectivity analyses can serve landscape planning with designing functional conservation networks. However, existing frameworks face challenges, such as achieving consistency between integrated data and modeled processes, implementing data-driven parameterization, and addressing connectivity within the home range. We propose restricting connectivity analyses to the home range scale to better relate landscape resistance, barrier effects and resource accessibility to daily movements and home range establishment.

We introduce a home range connectivity modeling framework that allows deriving important connectivity parameters empirically. We identify areas that can support home ranges based on available resources and calculate resource patch accessibility using graph and circuit theory. Resistance values, patch isolation distances, and connectivity metrics are selected from statistical models using movement data. We demonstrate the framework’s utility through a case study on urban blackbirds and increase its applicability by testing whether the use of simple presence/absence data without additional movement data, and the use of a coarser resolution affect the estimation of parameter values.

In statistical analyses, the local connectivity showed a strong significant positive association with the probability of blackbird movement (β = 0.23, p < 0.005). We uncover that the connectivity parameters are better assessed with graph theory-derived metrics when parametrized with movement data. We find a high barrier effect of high buildings and a moderate barrier effect of lower buildings and streets on blackbird movement. However, when assessed with presence/absence data, model parametrization can result in similar values only when using circuit theory metrics. Changing the resolution from 10 to 30 m has minimal impact on parametrization results with movement data.

Our study showcases a data-driven parameterization using statistical model selection, which addresses several of the main limitations of recent connectivity modeling approaches. Presence/absence data and coarser resolution can be used judiciously, but independently. Restricting analyses to home ranges yields valuable insights into home range ecology, landscape impacts on movement in highly heterogeneous landscapes, and species distribution.
Complex life cycles and parasite-mediated trophic cascades drive species coexistence and the maintenance of genetic diversity
Authors: Hijar-Islas Ana C. , Mon Père Nathaniel V. , Huang Weini , Eizaguirre Christophe
Published: December 2023

Ecological and evolutionary processes shape the dynamics of species interactions, yet the drivers of eco-evolutionary feedback remain elusive. Here, we developed an individual-based model of a coevolving predator-prey-parasite system, in which predators can be infected by trophically transmitted parasites. We combined host-parasite coevolution with prey-predator interactions at an individual level, hence integrating evolutionary and ecological processes. We show that species coexist more when parasite-mediated selection is weak on both the predator and the prey. Population size and genotypic diversity of the parasite are highest at intermediate parasite-mediated selection on the predator and no parasite-mediated selection on the prey. Interestingly, we show that the evolution of super-resistant genotypes, where host genotypes have resistant alleles in all loci, is driven by interspecific interactions rather than by the population size of the host species. Overall, host-parasite coevolution shapes the direction of interspecific ecological interactions which, in turn, determine species coexistence and community diversity in a complex system.
Investigating the impact of whole genome duplication on transposable element evolution in ray-finned fishes
Authors: Mallik Rittika , Wcisel Dustin J. , Near Thomas J. , Yoder Jeffrey A. , Dornburg Alex
Published: December 2023

Transposable elements (TEs) can make up more than 50% of any given vertebrate’s genome, with substantial variability in TE composition among lineages. TE variation is often linked to changes in gene regulation, genome size, and speciation. However, the role that genome duplication events have played in generating abrupt shifts in the composition of the mobilome over macroevolutionary timescales remains unclear. We investigated the degree to which the teleost genome duplication (TGD) shaped the diversification trajectory of the ray-finned fish mobilome. We integrate a new high coverage genome ofPolypterus bichirwith data from over 100 publicly available actinopterygian genomes to assess the macroevolutionary implications of genome duplication events on TE evolution. Our results provide no evidence for a substantial shift in mobilome composition following the TGD event. Instead, the diversity of the actinopterygian mobilome appears to have been shaped by a history of lineage specific shifts in composition that are not correlated with commonly evoked drivers of diversification such as body size, water column usage, or latitude. Collectively, these results provide a new perspective on the early diversification of the actinopterygian mobilome and suggest that historic ploidy events may not necessarily catalyze bursts of TE diversification and innovation.
Large scale, simultaneous, chronic neural recordings from multiple brain areas
Authors: Melin Maxwell D , Khanal Anup , Vasquez Marvin , Ryan Michael B , Churchland Anne K , Couto Joao
Published: December 2023

Understanding how brain activity is related to animal behavior requires measuring multi-area interactions on multiple timescales. However, methods to perform chronic, simultaneous recordings of neural activity from many brain areas are lacking.

Here, we introduce a novel approach for independent chronic probe implantation that enables flexible, simultaneous interrogation of neural activity from many brain regions during head restrained or freely moving behavior. The approach, that we calledindie(independentdovetail implants forelectrophysiology), enables repeated retrieval and reimplantation of probes. The chronic implantation approach can be combined with other modalities such as skull clearing for cortex wide access and optogenetics with optic fibers. Using this approach, we implanted 6 probes chronically in one hemisphere of the mouse brain.

The implant is lightweight, allows flexible targeting with different angles, and offers enhanced stability. Our approach broadens the applications of chronic recording while retaining its main advantages over acute recordings (superior stability, longitudinal monitoring of activity and freely moving interrogations) and provides an appealing venue to study processes not accessible by acute methods, such as the neural substrate of learning across multiple areas.
Open-ST: High-resolution spatial transcriptomics in 3D
Authors: Schott Marie , León-Periñán Daniel , Splendiani Elena , Strenger Leon , Licha Jan Robin , Pentimalli Tancredi Massimo , Schallenberg Simon , Alles Jonathan , Tagliaferro Sarah Samut , Boltengagen Anastasiya , Ehrig Sebastian , Abbiati Stefano , Dommerich Steffen , Pagani Massimiliano , Ferretti Elisabetta , Macino Giuseppe , Karaiskos Nikos , Rajewsky Nikolaus
Published: December 2023

Spatial transcriptomics (ST) methods have been developed to unlock molecular mechanisms underlying tissue development, homeostasis, or disease. However, there is a need for easy-to-use, high-resolution, cost-efficient, and 3D-scalable methods. Here, we report Open-ST, a sequencing-based, open-source experimental and computational resource to address these challenges and to study the molecular organization of tissues in 3D. In mouse brain, Open-ST captured transcripts at subcellular resolution and reconstructed cell types. In primary tumor and patient-matched healthy/metastatic lymph nodes, Open-ST captured the diversity of immune, stromal and tumor populations in space. Distinct cell states were organized around cell-cell communication hotspots in the tumor, but not the metastasis. Strikingly, the 3D reconstruction and multimodal analysis of the metastatic lymph node revealed spatially contiguous structures not visible in 2D and potential biomarkers precisely at the 3D tumor/lymph node boundary. We anticipate Open-ST to accelerate the identification of spatial molecular mechanisms in 2D and 3D.
Cellular Senescence Impairs Tendon Extracellular Matrix Remodeling in Response to Mechanical Unloading
Authors: Stowe Emma J. , Keller Madelyn R. , Connizzo Brianne K.
Published: December 2023

Musculoskeletal injuries, including tendinopathies, present a significant clinical burden for aging populations. While the biological drivers of age-related declines in tendon function are poorly understood, it is well accepted that dysregulation of extracellular matrix (ECM) remodeling plays a role in chronic tendon degeneration. Senescent cells, which have been associated with multiple degenerative pathologies in musculoskeletal tissues, secrete a highly pro-inflammatory senescence-associated secretory phenotype (SASP) that has potential to promote ECM breakdown. However, the role of senescent cells in the dysregulation of tendon ECM homeostasis is largely unknown. To assess this directly, we developed anin vitromodel of induced cellular senescence in murine tendon explants. This novel technique enables us to study the isolated interactions of senescent cells and their native ECM without interference from age-related systemic changes. We document multiple biomarkers of cellular senescence in induced tendon explants including cell cycle arrest, apoptosis resistance, and SASP production. We then utilize thisin vitrosenescence model to compare the ECM remodeling response of young, naturally aged, and senescent tendons to an altered mechanical stimulus. We found that both senescence and aging independently led to alterations in ECM-related gene expression, reductions in protein synthesis, and tissue compositional changes. Furthermore, MMP activity was sustained, thus shifting the remodeling balance of aged and senescent tissues towards degradation over production. Together, this demonstrates that cellular senescence plays a role in the altered mechano-response of aged tendons and likely contributes to poor clinical outcomes in aging populations.
Functional mapping of the somatosensory cortex using noninvasive fMRI and touch in awake dogs
Authors: Guran C.-N. Alexandrina , Boch Magdalena , Sladky Ronald , Lonardo Lucrezia , Karl Sabrina , Huber Ludwig , Lamm Claus
Published: December 2023

Dogs are increasingly used as a model for neuroscience due to their ability to undergo functional MRI fully awake and unrestrained, after extensive behavioral training. Still, we know rather little about dogs’ basic functional neuroanatomy, including how basic perceptual and motor functions are localized in their brains. This is a major shortcoming in interpreting activations obtained in dog fMRI. The aim of this preregistered study was to localize areas associated with somatosensory processing. To this end, we touched N = 22 dogs undergoing fMRI scanning on their left and right flanks using a wooden rod. We identified activation in anatomically defined primary and secondary somatosensory areas (SI and SII), lateralized to the contralateral hemisphere depending on the side of touch, as well as activations, beyond an anatomical mask of SI and SII, in the cingulate cortex, right cerebellum and vermis, and the Sylvian gyri. These activations may partly relate to motor control (cerebellum, cingulate), but also potentially to higher-order cognitive processing of somatosensory stimuli (rostral Sylvian gyri), and the affective aspects of the stimulation (cingulate). We also found evidence for individual side biases in a vast majority of dogs in our sample, pointing at functional lateralization of somatosensory processing. These findings not only provide further evidence that fMRI is suited to localize neuro-cognitive processing in dogs in vivo, but also expand our understanding of touch processing in mammals, beyond classically defined primary and secondary somatosensory cortices.

Significance Statement

To understand brain function and evolution, it is necessary to look beyond the human lineage. This study provides insights into the engagement of brain areas related to somatosensation using whole-brain non-invasive neuroimaging of trained, non-sedated, and unrestrained pet dogs. It showcases again the usefulness of non-invasive methods, in particular fMRI, for investigating brain function and advances the mapping of brain functions in dogs; using this non-invasive approach without sedation, we are able to identify previously unknown potential higher-order processing areas and offer a quantification of touch processing lateralization.
Reliability of task-based fMRI in the dorsal horn of the human spinal cord
Authors: Dabbagh Alice , Horn Ulrike , Kaptan Merve , Mildner Toralf , Müller Roland , Lepsien Jöran , Weiskopf Nikolaus , Brooks Jonathan C.W. , Finsterbusch Jürgen , Eippert Falk
Published: December 2023

The application of functional magnetic resonance imaging (fMRI) to the human spinal cord is still a relatively small field of research and faces many challenges. Here we aimed to probe the limitations of task-based spinal fMRI at 3T by investigating the reliability of spinal cord blood oxygen level dependent (BOLD) responses to repeated nociceptive stimulation across two consecutive days in 40 healthy volunteers. We assessed the test-retest reliability of subjective ratings, autonomic responses, and spinal cord BOLD responses to short heat pain stimuli (1s duration) using the intraclass correlation coefficient (ICC). At the group level, we observed robust autonomic responses as well as spatially specific spinal cord BOLD responses at the expected location, but no spatial overlap in BOLD response patterns across days. While autonomic indicators of pain processing showed good-to-excellent reliability, bothβ-estimates and z-scores of task-related BOLD responses showed poor reliability across days in the target region (gray matter of the ipsilateral dorsal horn). When taking into account the sensitivity of gradient-echo echo planar imaging (GE-EPI) to draining vein signals by including the venous plexus in the analysis, we observed BOLD responses with fair reliability across days. Taken together, these results demonstrate that heat pain stimuli as short as one second are able to evoke a robust and spatially specific BOLD response, which is however strongly variable within participants across time, resulting in low reliability in the dorsal horn gray matter. Further improvements in data acquisition and analysis techniques are thus necessary before event-related spinal cord fMRI as used here can be reliably employed in longitudinal designs or clinical settings.
Image-based computational fluid dynamics to compare two mitral valve reparative techniques for the prolapse
Authors: Bennati Lorenzo , Puppini Giovanni , Giambruno Vincenzo , Luciani Giovanni Battista , Vergara Christian
Published: December 2023

Objective

Nowadays, the treatment of mitral valve prolapse involves two distinct repair techniques: chordal replacement (Neochordae technique) and leaflet resection (Resection technique). However, there is still a debate in the literature about which is the optimal one. In this context, we performed an image-based computational fluid dynamic study to evaluate blood dynamics in the two surgical techniques.

Methods

We considered a healthy subject (H) and two patients (N and R) who underwent surgery for the prolapse of the posterior leaflet and were operated with the Neochordae and Resection technique, respectively. Computational Fluid Dynamics (CFD) was employed with prescribed motion of the entire left heart coming from cine-MRI images, with a Large Eddy Simulation model to describe the transition to turbulence and a resistive method for managing valve dynamics. We created three different virtual scenarios where the operated mitral valves were inserted in the same left heart geometry of the healthy subject to study the differences attributed only to the two techniques.

Results

We compared the three scenarios by quantitatively analyzing ventricular velocity patterns and pressures, transition to turbulence, and the ventricle ability to prevent thrombi formation. From these results we found that both the operated cases were able to restore almost physiological blood dynamic conditions, with some differences due to the reduced mobility of the Resection posterior leaflet. Conclusions: Our findings suggest that the Neochordae technique developed a slightly more physiological flow with respect to the Resection technique. The latter gave rise to a different direction of the mitral jet during diastole increasing the turbulence that is associated with ventricular effort and hemolysis, with also a larger ability to washout the ventricular apex preventing from thrombi formation.
Diroximel fumarate acts through Nrf2 to attenuate methylglyoxal-induced nociception in mice and decreases ISR activation in DRG neurons
Authors: Yousuf Muhammad Saad , Mancilla Moreno Marisol , Li Jiahe , He Lucy , Royer Danielle , Zhang Jennifer , Woodall Brodie J , Grace Peter M , Price Theodore J
Published: December 2023

Diabetic neuropathic pain is associated with elevated plasma levels of methylglyoxal (MGO). MGO is a metabolite of glycolysis that causes mechanical hypersensitivity in mice by inducing the integrated stress response (ISR), which is characterized by phosphorylation of eukaryotic initiation factor 2α (p-eIF2α). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the expression of antioxidant proteins that neutralize MGO. We hypothesized that activating Nrf2 using diroximel fumarate (DRF) would alleviate MGO-induced pain hypersensitivity. We pretreated male and female C57BL/6 mice daily with oral DRF prior to intraplantar injection of MGO (20 ng). DRF (100 mg/kg) treated animals were protected from developing MGO-induced mechanical and cold hypersensitivity. UsingNrf2knockout mice we demonstrate that Nrf2 is necessary for the anti-nociceptive effects of DRF. In cultured mouse and human dorsal root ganglion (DRG) sensory neurons, we found that MGO induced elevated levels of p-eIF2α. Co-treatment of MGO (1 µM) with monomethyl fumarate (MMF, 10, 20, 50 µM), the active metabolite of DRF, reduced p-eIF2α levels and prevented aberrant neurite outgrowth in human DRG neurons. Our data show that targeting the Nrf2 antioxidant system with DRF is a strategy to potentially alleviate pain associated with elevated MGO levels.

Perspective

This study demonstrates that activating Nrf2 with DRF prevents the development of pain caused by MGO in mice and reduces ISR in mouse and human DRGin vitromodels. We propose that Nrf2 activators like DRF should be tested to alleviate diabetic neuropathic pain associated with elevated MGO in patients.

Graphical Abstract

Article Highlights

MGO induces mechanical and cold hypersensitivity in mice that is prevented with pre-treatment with DRF.

DRF pre-treatment does not protect Nrf2-knockout mice from developing pain hypersensitivity suggesting that Nrf2 is necessary for DRF’s antinociceptive effects.

MMF, the active metabolite of DRF, prevents MGO-induced increase in p-eIF2a levels in mouse and human DRG neuronsin vitro.

MMF prevents MGO-induced aberrant neurite outgrowth in human DRG neurons.

Nrf2 activators, like the FDA-approved DRF, is an option to alleviate neuropathic pain in patients with diabetes.
Online stimulation of prefrontal cortex during practice increases motor variability and modulates later cognitive transfer: a randomized, double-blinded & sham-controlled tDCS study
Authors: Prabhu Nisha Maria , Lehmann Nico , Kaminski Elisabeth , Müller Notger , Taubert Marco
Published: December 2023

Background

The benefits of learning a motor skill extend to improved task-specific cognitive abilities. The mechanistic underpinnings of this motor-cognition relationship potentially rely on overlapping neural resources involved in both processes, an assumption lacking causal evidence.

Objectives

We hypothesize that interfering with prefrontal networks would affect concurrent motor skill performance, long-term learning and associated cognitive functions dependent on similar networks (transfer).

Methods

We conducted a randomized, double-blinded, sham-controlled brain stimulation study using transcranial direct current stimulation (tDCS) in young adults spanning over three weeks to assess the role of the prefrontal regions in learning a complex balance task and long-term cognitive performance.

Results

Balance training combined with active tDCS led to higher performance variability in the trained task as compared to the sham group, without affecting the learning rate. Furthermore, active tDCS also positively impacted performance in untrained motor and cognitive tasks.

Conclusion

The findings of this study help ascertaining the networks directly involved in learning a complex motor task and its implications on cognitive function. Hence, opening up the possibility of harnessing the observed frontal networks involved in resource mobilization in instances of aging, brain lesion/injury or dysfunction.
HyLight: Strain aware assembly of low coverage metagenomes
Authors: Kang Xiongbin , Zhang Wenhai , Luo Xiao , Schönhuth Alexander
Published: December 2023

Different strains of identical species can vary substantially in terms of their spectrum of biomedically relevant phenotypes. Reconstructing the genomes of a microbial community at strain level poses major methodical challenges, because relative frequencies of individual strains match the rate of sequencing errors, which hampers the identification of their characteristic genetic variants. While next-generation sequencing (NGS) reads are too short to span complex repetitive regions, the considerably longer third-generation sequencing (TGS) reads are affected by larger sequencing error rates or are just significantly more expensive. Suppressing TGS coverage to limit costs implies losses in terms of the accuracy of the assemblies. Therefore, existing approaches have remained fragmentary: all approaches presented so far agree on losses in strain awareness, accuracy, possibly excessive costs of the assemblies, or combinations thereof.

We present HyLight as, to the best of our knowledge, the first metagenome assembly approach that is not affected by any of the aforementioned drawbacks. In experiments, we demonstrate that HyLight assemblies are strain-aware, contiguous, contain little errors, and because operating on low coverage TGS data of the cheap kind, come at drastically reduced costs. HyLight implements hybrid assembly, which exploits the complementarity of TGS and NGS data. For unifying the two types of data, HyLight utilizes strain resolved overlap graphs (OG), which support the accurate reconstruction of the individual members of microbial communities at strain level: HyLight outperforms existing approaches in terms of strain identity preserving sequence by on average 25.53% (across all experiments / data sets: first quartile: 21.53%, median: 26.81%, third quartile: 31.98%), achieving near-complete strain awareness on many data sets. In summary, HyLight appears to implement the first protocol that delivers assemblies that are strain-aware, contiguous and accurate in combination.
Perceptual Foundation and Extension to Phase Tagging for Rapid Invisible Frequency Tagging (RIFT)
Authors: Spaak Eelke , Bouwkamp Floortje G. , de Lange Floris P.
Published: December 2023

Recent years have seen the emergence of a visual stimulation protocol called Rapid Invisible Frequency Tagging (RIFT) in cognitive neuroscience. In RIFT experiments, visual stimuli are presented at a rapidly and sinusoidally oscillating luminance, using high refresh rate projection equipment. Such stimuli result in strong steady-state responses in visual cortex, measurable extracranially using EEG or MEG. The high signal-to-noise ratio of these neural signals, combined with the alleged invisibility of the manipulation, make RIFT a potentially promising technique to study the neural basis of visual processing. In this study, we set out to resolve two fundamental, yet still outstanding, issues regarding RIFT; as well as to open up a new avenue for taking RIFT beyond frequency tagging per se. First, we provide robust evidence that RIFT is indeed subjectively undetectable, going beyond previous anecdotal reports. Second, we demonstrate that full-amplitude luminance or contrast manipulation offer the best tagging results. Third and finally, we demonstrate that, in addition to frequency tagging, phase tagging can reliably be used in RIFT studies, opening up new avenues for constructing RIFT experiments. Together, this provides a solid foundation for using RIFT in visual cognitive neuroscience.
Genetic evidence of a hybrid swarm between Alpine ibex and domestic goat
Authors: Brambilla Alice , Zehnder Noel , Bassano Bruno , Rossi Luca , Grossen Christine
Published: December 2023

Improving the understanding of the causes and effects of anthropogenic hybridization is fundamental to ensure the conservation of wild species, particularly in the case of hybridization between wild species and their domestic relatives. Knowledge is missing for many species also because of a lack of appropriate tools for hybrid identification. Here, coupling genotype and phenotype analysis, we carried out an extensive investigation of ongoing hybridization in Alpine ibexCapra ibex, a mountain ungulate of conservation concern from a genetic perspective. By genotyping at 63 diagnostic and 465 neutral SNPs 20 suspected hybrids and 126 Alpine ibex without suspicious phenotype, representing eight populations across a major part of the species distribution, we found evidence for ongoing hybridization between Alpine ibex and domestic goat. We identified different levels of hybridization including back crosses into both Alpine ibex and domestic goat. Our results suggest a lack of reproductive barriers between the two species and good survival and reproductive success of the hybrids. Hybridization was locally intense, alike a hybrid swarm, but not spread across the rest of the species distribution. Most of the hybrids were discovered in two locations in the North-West of Italy, while random sampling of individuals from different areas did not provide evidence of recent hybridization. Our method, based on Amplicon sequencing of 63 diagnostic SNPs specifically developed for this purpose, allowed us to identify hybrids and back crosses up to the 4th-5thgeneration and was suitable for genetic samples of different quality, although with varying levels of certainty regarding the exact number of generations passed since hybridization. Based on the paired analysis of genotype and phenotype we provide guidelines for a first identification of hybrids in the field and suggest a procedure for the reliable identification of hybrids.
Sweet and fatty symbionts: photosynthetic productivity and carbon storage boosted in microalgae within a host
Authors: Catacora-Grundy A. , Chevalier F. , Yee D. , LeKieffre C. , Schieber N. L. , Schwab Y. , Gallet B. , Jouneau P.H. , Curien G. , Decelle J.
Published: December 2023

Symbiosis between a host and intracellular eukaryotic microalgae is a widespread life strategy in aquatic ecosystems. This partnership is considered to be mainly energized by the photosynthetically-derived carbon energy of microalgal symbionts. A major question is whether microalgae increase their photosynthetic production and decrease carbon storage in order to maximize carbon translocation to their host. By combining three-dimensional subcellular imaging and physiological analyses, we show that the photosynthetic machinery (chloroplast and CO2-fixing pyrenoid) of the symbiotic microalgaMicractinium conductrixsignificantly expands inside their host (the ciliateParamecium bursaria) compared to the free-living state. This is accompanied by a 13-fold higher quantity of Rubisco enzymes and 16-fold higher carbon fixation rate. Time-resolved subcellular imaging revealed that photosynthetically-derived carbon is first allocated to starch during the day, with five times higher production in symbiosis despite low growth. Nearly half of the carbon stored in starch is consumed overnight and some accumulates in lipid droplets, which are 20-fold more voluminous in symbiotic microalgae. We also show that carbon is transferred to the host and hypothesize that much of this is respired by the high density of surrounding host mitochondria. We provide evidence that the boosted photosynthetic production of symbiotic microalgae could be explained by the energetic demands of the host. Overall, this study provides an unprecedented view of the subcellular remodeling and dynamics of carbon metabolism of microalgae inside a host, highlighting the potentially key role of the source-sink relationship in aquatic photosymbiosis.

Significance statement

Symbiotic interactions between a heterotrophic host and intracellular microalgae are widespread in aquatic ecosystems and are considered to be energized by the photosynthetically-derived carbon energy. However, little is known on the impact of symbiosis on the algal bioenergetics (e.g. carbon production and storage). This study reveals the morphological and physiological changes of a microalga inside a host at the subcellular scale over the day. We show that the photosynthetic machinery expands and carbon fixation and storage are boosted in symbiotic microalgae beyond their growth needs. This high photosynthetic production is very likely enhanced by the host energetic demands. Our findings advance our basic understanding of photosymbiosis and open new perspectives on the mechanisms and drivers of metabolic exchange between partners.
Single-molecule imaging and molecular dynamics simulations reveal early activation of the MET receptorin situ
Authors: Li Yunqing , Arghittu Serena , Dietz Marina S. , Hella Gabriel J. , Haße Daniel , Ferraris Davide M. , Freund Petra , Barth Hans-Dieter , Niemann Hartmut H. , Covino Roberto , Heilemann Mike
Published: December 2023

The assembly of membrane receptors into signaling complexes is at the origin of key cellular events. Yet, we often lack detailed structural mechanistic understanding. Receptors are embedded into a complex cellular membrane, which defines their dynamics but also complicates their experimental characterizations significantly. Here, we showcase an integrative structural biology approach to investigate the activation mechanism of the human growth factor receptor MET. MET is a receptor tyrosine kinase involved in cell proliferation, migration, and survival. MET is also hijacked by the intracellular pathogenListeria monocytogenes. Its invasion protein, internalin B (InlB), binds to MET and promotes the formation of a signaling dimer that triggers the internalization of the pathogen. Crystallography had suggested two different 2:2 MET:InlB complexes. Here, we use a combination of structural biology, modeling, molecular dynamics simulations, andin situsingle-molecule Förster resonance energy transfer (smFRET) to elucidate the early events in MET activation. Simulations show that InlB binding stabilizes MET in a conformation that promotes dimer formation. smFRET identifies the organization of thein situsignaling dimer, which resembles one of the two crystal structures yet shows differences. Further MD simulations resulted in a refinement of the dimer model, which is in quantitative agreement with smFRET results. We accurately describe the structural dynamics underpinning an important cellular event and introduce a powerful methodological pipeline applicable to studying the activation of other plasma membrane receptorsin situ.
Integration of Multi-omics Data for the Classification of Glioma Types and Identification of Novel Biomarkers
Authors: Vieira Francisca G. , Bispo Regina , Lopes Marta B.
Published: December 2023

Glioma is currently one of the most prevalent types of primary brain cancer. Given its high level of heterogeneity along with the complex biological molecular markers, many efforts have been made to accurately classify the type of glioma in each patient, which, in turn, is critical to improve early diagnosis and increase survival. Nonetheless, as a result of the fast-growing technological advances in high throughput sequencing and evolving molecular understanding of glioma biology, its classification has been recently subject to significant alterations. In this study, we integrate multiple glioma omics modalities (including mRNA, DNA methylation, and miRNA) from The Cancer Genome Atlas (TCGA), while using the revised glioma reclassified labels, with a supervised method based on sparse canonical correlation analysis (DIABLO) to discriminate between glioma types. We were able to find a set of highly correlated features distinguishing glioblastoma from lower-grade gliomas (LGG) that were mainly associated with the disruption of receptor tyrosine kinases signaling pathways and extracellular matrix organization and remodeling. On the other hand, the discrimination of the LGG types was characterized primarily by features involved in ubiquitination and DNA transcription processes. Furthermore, we could identify several novel glioma biomarkers likely helpful in both diagnosis and prognosis of the patients, including the genesPPP1R8, GPBP1L1, KIAA1614, C14orf23, CCDC77, BVES, EXD3, CD300AandHEPN1. Overall, this classification method allowed to discriminate the different TCGA glioma patients with very high performance, while seeking for common information across multiple data types, ultimately enabling the understanding of essential mechanisms driving glioma heterogeneity and unveiling potential therapeutic targets.
Bidirectional relationship between attentional deficits and escalation of nicotine intake
Authors: Vouillac-Mendoza Caroline , Ahmed Serge H. , Guillem Karine
Published: December 2023

Smoking addicts have deficits in cognition, in particular deficits in attention, even long after smoking cessation. It is not clear however, whether deficits are a cause or a consequence, or both, of chronic nicotine use. Here we set out a series of experiments in rats to address this question and, more specifically, to assess the long-term effects of exposure to and withdrawal from chronic nicotine self-administration on attentional performance. Animals were trained in a 5-choice serial reaction time task to probe individual attentional performance and, then, were given access to a fixed versus increasing dose of intravenous nicotine for self-administration, a differential dose procedure known to induce two between-session patterns of nicotine intake: a stable versus escalation pattern. Attentional performance was measured daily before, during and also 24-h after chronic access to the differential dose procedure of nicotine self-administration. We found that pre-existing individual variation in attentional performance predicts individual vulnerability to develop escalation of nicotine intake. Moreover, while chronic nicotine self-administration increases attention, withdrawal from nicotine intake escalation induces attentional deficits, a withdrawal effect that is dose-dependently reversed by acute nicotine. Together, these results suggest that pre-existing individual variation in attentional performance predicts individual vulnerability to develop escalation of nicotine intake, and that part of the motivation for using nicotine during escalation might be to alleviate withdrawal-induced attentional deficits.
WildCLIP: Scene and animal attribute retrieval from camera trap data with domain-adapted vision-language models
Authors: Gabeff Valentin , Rußwurm Marc , Tuia Devis , Mathis Alexander
Published: December 2023

Wildlife observation with camera traps has great potential for ethology and ecology, as it gathers data non-invasively in an automated way. However, camera traps produce large amounts of uncurated data, which is time-consuming to annotate. Existing methods to label these data automatically commonly use a fixed pre-defined set of distinctive classes and require many labeled examples per class to be trained. Moreover, the attributes of interest are sometimes rare and difficult to find in large data collections. Large pretrained vision-language models, such as Contrastive Language Image Pretraining (CLIP), offer great promises to facilitate the annotation process of camera-trap data. Images can be described with greater detail, the set of classes is not fixed and can be extensible on demand and pretrained models can help to retrieve rare samples. In this work, we explore the potential of CLIP to retrieve images according to environmental and ecological attributes. We create WildCLIP by fine-tuning CLIP on wildlife camera-trap images and to further increase its flexibility, we add an adapter module to better expand to novel attributes in a few-shot manner. We quantify WildCLIP’s performance and show that it can retrieve novel attributes in the Snapshot Serengeti dataset. Our findings outline new opportunities to facilitate annotation processes with complex and multi-attribute captions. The code will be made available athttps://github.com/amathislab/wildclip.
Dual carbon sequestration with photosynthetic living materials
Authors: Dranseike Dalia , Cui Yifan , Ling Andrea S. , Donat Felix , Bernhard Stéphane , Bernero Margherita , Areeckal Akhil , Qin Xiao-Hua , Oakey John S. , Dillenburger Benjamin , Studart André R. , Tibbitt Mark W.
Published: December 2023

Natural ecosystems offer efficient pathways for carbon sequestration, serving as a resilient approach to remove CO2from the atmosphere with minimal environmental impact. However, the control of living systems outside of their native environments is often challenging. Here, we engineered a photosynthetic living material for dual CO2sequestration by immobilizing photosynthetic microorganisms within a printable polymeric network. The carbon concentrating mechanism of the cyanobacteria enabled accumulation of CO2within the cell, resulting in biomass production. Additionally, the metabolic production of OH-ions in the surrounding medium created an environment for the formation of insoluble carbonates via microbially-induced calcium carbonate precipitation (MICP). Digital design and fabrication of the living material ensured sufficient access to light and nutrient transport of the encapsulated cyanobacteria, which were essential for long-term viability (more than one year) as well as efficient photosynthesis and carbon sequestration. The photosynthetic living materials sequestered approximately 2.5 mg of CO2per gram of hydrogel material over 30 days via dual carbon sequestration, with 2.2 ± 0.9 mg stored as insoluble carbonates. Over an extended incubation period of 400 days, the living materials sequestered 26 ± 7 mg of CO2per gram of hydrogel material in the form of stable minerals. These findings highlight the potential of photosynthetic living materials for scalable carbon sequestration, carbon-neutral infrastructure, and green building materials. The simplicity of maintenance, coupled with its scalability nature, suggests broad applications of photosynthetic living materials as a complementary strategy to mitigate CO2emissions.
Brg1 regulates fibroblast-myofibroblast transition to promote renal fibrosis
Authors: Wu Xiaoyan , Luo Yajun , Kang Aoqi , Ni Jiayao , Kong Ming , Zhang Tao
Published: December 2023

Excessive fibrogenesis serves to disrupt the anatomical and functional integrity of the kidneys contributing to renal failure. Renal fibroblast is the major precursor to myofibroblast, the effector cell type of renal fibrosis. How fibroblast-myofibroblast transition (FMyT) is regulated in the kidneys remains incompletely understood. In the present study we investigated the role of Brahma related gene 1 (Brg1), a chromatin remodeling protein, in renal fibrosis focusing on mechanistic insights and translational potential. We report that Brg1 was up-regulated during FMyT bothin vitroandin vivo. Brg1 deletion in fibroblasts partially blocked TGF-β induced FMyTin vitroand attenuated renal fibrosis in three different animal models. Importantly, conditional Brg1 knockout inPostn+mature myofibroblasts mitigated renal fibrosis induced by unilateral ureteral obstruction (UUO) or ischemia-reperfusion (IR) in mice. Transcriptomic analysis uncovered Prune2 as a potential target for Brg1. Brg1 interacted with E2F1 to activate Prune2 transcription during FMyT. Concordantly, Prune2 knockdown suppressed TGF-β induced FMyTin vitroand dampened renal fibrosis in mice. Mechanistically, Prune2 likely contributed to FMyT by augmenting phosphorylation and activity of the pro-fibrogenic transcription factor PU.1. Finally, small-molecule Brg1 inhibitor PFI-3 exhibited strong antifibrotic potency in established models of renal fibrosis. In conclusion, our data provide compelling evidence that BRG1 is a pivotal regulator of as well as a promising therapeutic target for renal fibrosis.