bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping Eelgrass Cover and Biomass at Izembek Lagoon, Alaska, Using In-situ Field Data and Sentinel-2 Satellite Imagery
Authors: Douglas David C. , Fleming Michael D. , Patil Vijay P. , Ward David H.
Published: August 2024

Two eelgrass (Zostera marina) maps of Izembek Lagoon, Alaska, were generated by first creating maps of spectrally unique classes from each of two Sentinel-2 satellite images collected on July 1, 2016, and August 14, 2020, then attributing the spectral classes with information about eelgrass conditions based on field data. Maps depicting various eelgrass metrics, such as percent cover and modeled biomass, were generated using summaries of the ground data that spatially intersected each spectral class. Comparisons between the 2016 and 2020 Sentinel-2 maps of eelgrass distributional extent, as well as a 2006 Landsat map, indicated that areas where eelgrass presence may have declined between 2006 and 2020 were most prevalent in the central part Izembek Lagoon, while areas of possible biomass decline were more prevalent in the southern part between 2016 and 2020. Monitoring eelgrass conditions at Izembek Lagoon with satellite imagery and concurrent ground data provides capabilities for making comparisons over time, but the influences of tide levels, growing season phenology, and spatiotemporal co-registration accuracy should be considered when designing and interpreting change detection analyses.
Identity-by-descent (IBD) segment outlier detection in endogamous populations using pedigree cohorts
Authors: Tan Shi Jie Samuel , Dang Huyen Trang , Keim Sarah , Bućan Maja , Mathieson Sara
Published: August 2024

Genomic segments that are inherited from a common ancestor are referred to as identical-by-descent (IBD). Because these segments are inherited, they not only allow us to study diseases, population characteristics, and the sharing of rare variants, but also understand hidden familial relationships within populations. Over the past two decades, various IBD finding algorithms have been developed using hidden Markov models (HMMs), hashing and extension, and Burrows-Wheeler Transform (BWT) approaches. In this study, we investigate the utility of pedigree information in IBD outlier detection methods for endogamous populations. With the increasing prevalence of computationally efficient sequencing technology and proper documentation of pedigree structures, we expect complete pedigree information to become readily available for more populations. While IBD segments have been used toreconstructpedigrees, because we now have access to the pedigree, it is a natural question to ask if including pedigree information would substantially improve IBD segment finding for the purpose of studying inheritance. We propose an IBD pruning algorithm for reducing the number of false positives in IBD segments detected by existing software. While existing software already identify IBD segments with high success rates, our algorithm analyzes the familial relationships between cohorts of individuals who are initially hypothesized to share IBD segments to remove outliers. Our algorithm is inspired by a k-Nearest Neighbors (kNN) approach with a novel distance metric for pedigrees with loops. We apply our method to simulated genomic data under an Amish pedigree, but it could be applied to pedigrees from other human populations as well as domesticated animals such as dogs and cattle.
Calculation of minimum energy pathways in transport proteins
Authors: Yorke Briony A , Ginn Helen M
Published: August 2024

1

Diverse conformations of highly populated protein metastable states are well-studied, but the fleeting transitions between these states cannot be observed by experimental methods or molecular dynamics simulations. To address this, we present a computationally inexpensive algorithm, “cold-inbetweening”, which generates trajectories in torsion angle space, by minimising the overall kinetic energy needed to complete a transition between experimentally determined end-states. Here we demonstrate the application of cold-inbetweening to provide mechanistic insight into the ubiquitous alternate access model of operation in three membrane transporter superfamilies. The model proposes mutually exclusive outward and inward pore opening, allowing ligand translocation but preventing damage from free solvent flow. Here, we study DraNramp fromDeinococcus radiodurians, MalT fromBacillus cereus, and MATE fromPyrococcus furiosus. In MalT, the trajectory demonstrates elevator transport through unwinding of a supporter arm helix, maintaining adequate space to transport maltose. In DraNramp, outward-gate closure occurs prior to inward-gate opening, in agreement with the alternate access model. In the MATE transporter, switching conformation involves obligatory rewinding of an extended N-terminal helix to avoid steric backbone clashes. This concurrently plugs the cavernous ligand-binding site during the conformational change. More generally, cold-inbetweening can be used to inform hypotheses about large functionally relevant conformational changes.
Single-cell multidimensional profiling of tumor cell heterogeneity in supratentorial ependymomas
Authors: Jeong Daeun , Danielli Sara G. , Maaß Kendra K. , Ghasemi David R. , Tetzlaff Svenja K. , Reyhan Ekin , Oliveira de Biagi-Junior Carlos Alberto , Neyazi Sina , Nascimento Andrezza , Haase Rebecca , Lo Cascio Costanza , Englinger Bernhard , Jiang Li , Nguyen Cuong M. , Baumgartner Alicia-Christina , Castellani Sophia , Rozowsky Jacob S. , Hack Olivia A. , Shaw McKenzie L. , Lotsch-Gojo Daniela , Bruckner Katharina , Pfister Stefan M. , Kool Marcel , Nowakowski Tomasz J. , Gojo Johannes , Baird Lissa , Alexandrescu Sanda , Pajtler Kristian W. , Venkataramani Varun , Filbin Mariella G.
Published: August 2024

Supratentorial ependymomas are aggressive childhood brain cancers that retain features of neurodevelopmental cell types and segregate into molecularly and clinically distinct subgroups, suggesting different developmental roots. The developmental signatures as well as microenvironmental factors underlying aberrant cellular transformation and behavior across each supratentorial ependymoma subgroup are unknown. Here we integrated single cell- and spatial transcriptomics, as well asin vitroandin vivolive-cell imaging to define supratentorial ependymoma cell states, spatial organization, and dynamic behavior within the neural microenvironment. We find that individual tumor subgroups harbor two distinct progenitor-like cell states reminiscent of early human brain development and diverge in the extent of neuronal or ependymal differentiation. We further uncover several modes of spatial organization of these tumors, including a high order architecture influenced by mesenchymal and hypoxia signatures. Finally, we identify an unappreciated role for brain-resident cells in shifting supratentorial ependymoma cellular heterogeneity towards neuronal-like cells that co-opt immature neuronal morphology and invasion mechanisms. Collectively, these findings provide a multidimensional framework to integrate transcriptional and phenotypic characterization of tumor heterogeneity in supratentorial ependymoma and its potential clinical implications.
A minimal mathematical model for polarity establishment and centralspindlin-independent cytokinesis
Authors: Maxian Ondrej , Longhini Katrina M , Glotzer Michael
Published: August 2024

Cell polarization and cytokinesis are fundamental processes in organismal development. In theCaenorhabditis elegansmodel system, both processes are partially driven by a local inhibition of contractility at the cell poles. Polarization is triggered by centrosome-directed, local inhibition of cortical contractility at what becomes the posterior pole, inducing cortical flows towards the anterior. In cytokinesis, spindle elongation-dependent astral relaxation combines with centralspindlin-induced accumulation of myosin at the cell equator to set up a robust contractility gradient. During both processes, inhibition of contractility occurs through Aurora A (AIR-1) kinase, which is activated on the centrosomes and diffuses to the cortex, where it inhibits the guanine nucleotide exchange factor (GEF) ECT-2, which generates actomyosin-based contractility by activating the GTPase RHO-1. While these biochemical processes have been characterized experimentally, a quantitative understanding of how this circuit drives cortical dynamics in polarization and cytokinesis is still lacking. Here, we construct a mathematical model to test whether a minimal set of well characterized, essential elements are necessary and sufficient to explain the spatiotemporal dynamics of AIR-1, ECT-2, and myosin during polarization and cytokinesis ofC. elegans. We show that robust establishment of polarity can be obtained in response to a weak AIR-1 signal, and demonstrate the relevance of rapid ECT-2 exchange and a persistent AIR-1 cue during polarization. The tuned model also correctly predicts previously-observed ultrasensitive ECT-2 dynamics during cytokinesis, suggesting quantitatively that the same minimal circuit operates in both processes.
LimbNET: collaborative platform for simulating spatial patterns of gene networks in limb development
Authors: Matyjaszkiewicz Antoni , Sharpe James
Published: August 2024

Successful computational modelling of complex biological phenomena will depend on the seamless sharing of models and hypotheses among researchers of all backgrounds - experimental and theoretical. LimbNET, a new online tool for modelling, simulating and visualising spatiotemporal patterning in limb development, aims to facilitate this process within the limb development community. LimbNET enables remote users to define and simulate arbitrary gene regulatory network (GRN) models of 2D spatiotemporal developmental patterning processes. Researchers can test and compare each others’ hypotheses - GRNs and predicted spatiotemporal patterns - within a common framework. A database of previously created models empowers users to simulate, explore, and extend each others’ work. Spatiotemporally-varying gene expression intensities, derived from image-based data, are mapped into a standardised computational description of limb growth, integrated within our modelling framework. This enables direct comparison not only between datasets but between data and simulation outputs, closing the feedback loop between experiments and simulation via parameter optimisation. All functionality is accessible through a web browser, requiring no special software, and opening the field of image-driven modelling to the full scientific community.
Microfluidic creep experiment for measuring linear viscoelastic mechanical properties of microparticles in a cross-slot extensional flow device
Authors: Mamaghani Sara Ghanbarpour , Dahl Joanna B.
Published: August 2024

The micromechanical measurement field has struggled to establish repeatable techniques, likely because the deforming stresses can be complicated and difficult to model. Here we demonstrate experimentally the ability of cross-slot microfluidic device to create a quasi-steady deformation state in agarose hydrogel microparticles to replicate a traditional uniaxial creep test at the microscale and at relatively high throughput. A recent numerical study by Lu et al. [Lu, Guo, Yu, Sui.J. Fluid Mech., 2023, 962, A26] showed that viscoelastic capsules flowing through a cross-slot can achieve a quasi-steady strain near the extensional flow stagnation point that is equal to the equilibrium static strain, thereby implying that continuous operation of a cross-slot can accurately capture capsule elastic mechanical behavior in addition to transient behavior. However, no microfluidic cross-slot studies have reported quasi-steady strains for suspended cells or particles, to our knowledge. By using large dimension cross-slots relative to the microparticle diameter, our cross-slot implementation created an extensional flow region that was large enough for agarose hydrogel microparticles to achieve a strain plateau while dwelling near the stagnation point. This strain plateau will be key for accurately and precisely measuring linear viscoelastic properties of small microscale biological objects. The mechanical test was performed in the linear regime, so an analytical mechanical model derived using the elastic-viscoelastic correspondence principle was proposed to extract linear viscoelastic mechanical properties from observed particle strain histories. Particle image velocimetry measurements of the unperturbed velocity field were used to determine where in the device particles experienced extensional flow and the mechanical model should be applied. The measurement throughput in this work was 1 – 2 particles achieving a quasi-steady strain plateau per second, though measurement yield and throughput can be increased with particle-centering upstream device design features. Finally, we provide recommendations for applying the cross-slot microscale creep experiment to other biomaterials and criteria to identify particles that likely achieved a quasi-steady strain state.
A Versatile Antibody Capture System that Drives PreciseIn Vivo Delivery of mRNA loaded Lipid Nanoparticles and Enhances Gene Expression
Authors: Chen Moore Z. , Yuen Daniel , McLeod Victoria M. , Yong Ken W. , Smyth Cameron H. , Herling Bruna Rossi , Payne Thomas. J. , Fabb Stewart A. , Belousoff Matthew J. , Algarni Azizah , Sexton Patrick M. , Porter Christopher J. H. , Pouton Colin W. , Johnston Angus P. R.
Published: August 2024

Efficient and precise delivery of mRNA is critical to advance mRNA therapies beyond their current use as vaccines. Lipid nanoparticles (LNP) efficiently encapsulate and protect mRNA, but non-specific cellular uptake may lead to off-target delivery and minimal delivery to target cells. Functionalizing LNPs with antibodies enables targeted mRNA delivery, but traditional modification techniques require complex conjugation and purification, which often reduces antibody affinity. Here, we present a simple method for capturing antibodies in their optimal orientation on LNPs, without antibody modification or complex purification. This strategy uses an optimally oriented anti-Fc nanobody on the LNP surface to capture antibodies, resulting in protein expression levels >1000 times higher than non-targeted LNPs and >8 times higher than conventional antibody functionalization techniques. These precisely targeted LNPs showed highly efficientin vivotargeting to T cells, with minimal delivery to other immune cells. This approach enables the rapid development of targeted LNPs and has the potential to broaden the use of mRNA therapies.
Global distribution and diversity of haloarchaeal pL6-family plasmids
Authors: Dyall-Smith Mike , Pfeiffer Friedhelm
Published: August 2024

Australian isolates ofHaloquadratum walsbyi, a square-shaped haloarchaeon, often harbor small cryptic plasmids of the pL6-family, approximately 6 kb in size. These plasmids exhibit a highly conserved gene arrangement and encode a replicase similar to those of betapleolipoviruses. To assess their global distribution and recover more examples for analysis, fifteen additional plasmids were reconstructed from the metagenomes of seven hypersaline sites across four countries: Argentina, Australia, Puerto Rico, and Spain. Including the five previously described plasmids, the average plasmid size is 6,002 bp, with an average G+C content of 52.5%. The tetramers GGCC and CTAG are either absent or significantly under-represented, except in the two plasmids with the highest %G+C. All plasmids share a similar arrange-ment of genes organized as outwardly facing replication and ATPase modules, but variations were observed in some core genes, such as F2, and some plasmids had acquired accessory genes. Two plasmids, pCOLO-c1 and pISLA-c6 shared 92.7% nt identity despite originating from Argentina and Spain, respectively. Numerous metagenomic CRISPR spacers matched sequences in the fifteen reconstructed plasmids, indicating frequent invasion of haloarchaea. Spacers could be assigned to haloarchaeal genera by mapping their associated direct repeats (DR), with half of these matching toHaloquadratum. Finally, strand-specific metatranscriptome (RNA-seq) data could be used to demonstrate the active transcription of two pL6-family plasmids, including antisense transcripts.
Integrated germline and somatic molecular profiling to detect cancer predisposition has a high clinical impact in poor-prognosis paediatric cancer
Authors: Fuentes-Bolanos Noemi A , Courtney Eliza , Mayoh Chelsea , Warby Meera , Lau Loretta M S , Wong-Erasmus Marie , Khuong-Quang Dong-Anh , Barahona Paulette , Padhye Bhavna , El-Kamand Sam , Nunag Sheena , Ajuyah Pamela , Sherstyuk Alexandra , Altekoester Ann-Kristin , Sullivan Ashleigh , Poplawski Nicola , Kiraly-Borri Catherine , O’Sullivan Sarah , Marfan Helen , Alli Rozanna , Curnow Lisette , Bhatia Kanika , Anazodo Antoinette , Trahair Toby N , Mateos Marion , Hansford Jordan R. , Dholaria Hetal , Josephi-Taylor Sarah , Moore Andrew S , Nicholls Wayne , Gottardo Nicholas G , Downie Peter , Khaw Seong-Lin , Tapp Heather , McCowage Geoffrey , Dalla-Pozza Luciano , Alvaro Frank , Wood Paul J , Tyrrell Vanessa , Haber Michelle , Cowley Mark J , Ekert Paul G , Marshall Glenn M , Kirk Judy , Tucker Katherine , Pinese Mark , Ziegler David S
Published: August 2024

Germline predisposition has a significant role in paediatric cancer. However, the optimal approach to identifying cancer-causing germline pathogenic variants (GPV) in children, and even the prevalence of GPV among children with cancer, remain unclear. Here we report our findings from a comprehensive survey of GPV in 496 children with poor-prognosis cancer. By integrating tumour and germline molecular profiling we identified GPV in 15.5% of patients, 48.1% of whom had not met clinical genetic testing criteria. Although the cancer type was outside the recognised phenotypic spectrum for 43.7% of reported GPV, 63.2% of these were clinically actionable for cancer risk. Integrated germline-tumour analysis increased the GPV detection rate by 8.5%, and informed germline interpretation in 14.3% of patients with GPV, highlighting the value of integrated analyses. Our findings establish the benefit of broad integrated tumour-germline screening, over phenotype-guided testing, to detect GPV in children with poor prognosis cancers.
Advancing oncology with federated learning: transcending boundaries in breast, lung, and prostate cancer. A systematic review
Authors: Ankolekar Anshu , Boie Sebastian , Abdollahyan Maryam , Gadaleta Emanuela , Hasheminasab Seyed Alireza , Yang Guang , Beauville Charles , Dikaios Nikolaos , Kastis George Anthony , Bussmann Michael , Khalid Sara , Kruger Hagen , Lambin Philippe , Papanastasiou Giorgos
Published: August 2024

Federated Learning (FL) has emerged as a promising solution to address the limitations of centralised machine learning (ML) in oncology, particularly in overcoming privacy concerns and harnessing the power of diverse, multi-center data. This systematic review synthesises current knowledge on the state-of-the-art FL in oncology, focusing on breast, lung, and prostate cancer. Distinct from previous surveys, our comprehensive review critically evaluates the real-world implementation and impact of FL on cancer care, demonstrating its effectiveness in enhancing ML generalisability, performance and data privacy in clinical settings and data. We evaluated state-of-the-art advances in FL, demonstrating its growing adoption amid tightening data privacy regulations. FL outperformed centralised ML in 15 out of the 25 studies reviewed, spanning diverse ML models and clinical applications, and facilitating integration of multi-modal information for precision medicine. Despite the current challenges identified in reproducibility, standardisation and methodology across studies, the demonstrable benefits of FL in harnessing real-world data and addressing clinical needs highlight its significant potential for advancing cancer research. We propose that future research should focus on addressing these limitations and investigating further advanced FL methods, to fully harness data diversity and realise the transformative power of cutting-edge FL in cancer care.
15 Years of Longitudinal Genetic, Clinical, Cognitive, Imaging, and Biochemical Measures in DIAN
Authors: Daniels Alisha J. , McDade Eric , Llibre-Guerra Jorge J. , Xiong Chengjie , Perrin Richard J. , Ibanez Laura , Supnet-Bell Charlene , Cruchaga Carlos , Goate Alison , Renton Alan E. , Benzinger Tammie L.S. , Gordon Brian A. , Hassenstab Jason , Karch Celeste , Popp Brent , Levey Allan , Morris John , Buckles Virginia , Allegri Ricardo F. , Chrem Patricio , Berman Sarah B. , Chhatwal Jasmeer P. , Farlow Martin R. , Fox Nick C. , Day Gregory S. , Ikeuchi Takeshi , Jucker Mathias , Lee Jae-Hong , Levin Johannes , Lopera Francisco , Takada Leonel , Sosa Ana Luisa , Martins Ralph , Mori Hiroshi , Noble James M. , Salloway Stephen , Huey Edward , Rosa-Neto Pedro , Sánchez-Valle Raquel , Schofield Peter R. , Roh Jee Hoon , Bateman Randall J. ,   the Dominantly Inherited Alzheimer Network
Published: August 2024

This manuscript describes and summarizes the Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs), highlighting the wealth of longitudinal data, samples, and results from this human cohort study of brain aging and a rare monogenic form of Alzheimer’s disease (AD). DIAN Obs is an international collaborative longitudinal study initiated in 2008 with support from the National Institute on Aging (NIA), designed to obtain comprehensive and uniform data on brain biology and function in individuals at risk for autosomal dominant AD (ADAD). ADAD gene mutations in the amyloid protein precursor (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes are deterministic causes of ADAD, with virtually full penetrance, and a predictable age at symptomatic onset. Data and specimens collected are derived from full clinical assessments, including neurologic and physical examinations, extensive cognitive batteries, structural and functional neuro-imaging, amyloid and tau pathological measures using positron emission tomography (PET), flurordeoxyglucose (FDG) PET, cerebrospinal fluid and blood collection (plasma, serum, and whole blood), extensive genetic and multi-omic analyses, and brain donation upon death. This comprehensive evaluation of the human nervous system is performed longitudinally in both mutation carriers and family non-carriers, providing one of the deepest and broadest evaluations of the human brain across decades and through AD progression. These extensive data sets and samples are available for researchers to address scientific questions on the human brain, aging, and AD.
“Safety and Efficacy of Exercise-based cardiac rehabilitation in patients with refractory angina: a randomized, controlled trial”
Authors: Dourado Luciana Oliveira Cascaes , Jordão Camila Paixão , Vieira Marcelo Luiz Campos , Gowdak Luis Henrique Wolff , Negrão Carlos Eduardo , de Matos Luciana Diniz Nagem Janot
Published: August 2024

Aim

Evidence is scarce regarding safety and anti-ischemic effects of exercise-based cardiac rehabilitation (ECR) in patients with refractory angina (RA).

Methods

This was a prospective, single-center, randomized controlled study that assessed a 12-week ECR program in patients with RA. Death and cardiovascular events, anginal symptoms, exercise stress echocardiogram (ESE) and cardiopulmonary exercise test (CPET) parameters were evaluated. When significant differences were detected, Bonferroni post hoc comparisons were conducted.

Results

No difference regarding clinical events and anginal symptoms was found between groups. In ESE, rehab group (RG) increased in peak load (RGpostto RGpre,P= 0.001; interaction,P< 0.001), angina quantification (RGpostto RGpre,P= 0.004; control group (CG)prethan CGpost,P= 0.006; RGpostthan CGpre,P= 0.0019; interaction,P= 0.001), exercise duration (RGpostto RGpre,P= 0.009; interaction,P= 0.006), ischemic threshold (RGpostto RGpre,P= 0.001; CGprethan CGpost,P= 0.03; RGpostthan CGpre,P= 0.008; interaction,P= 0.005) and angina threshold (RGpostto RGpre,P= 0.04; RGpostthan CGpost,P= 0.04; interaction,P= 0.002). In CPET, RG had increased exercise duration and covered distance in RGpost(RGprethan RGpost,P= 0.001; interaction,P= 0.014, RGprethan RGpost,P< 0.001; interaction,P< 0.01; respectively).

Conclusion

A 12-week ECR was safe and promoted positive clinical effects regarding exercise duration, intensity of angina, and angina and ischemic thresholds in RA patients.

The trial registry: Cardiac Rehabilitation in Patients with Refractory Angina (NCT03218891)
Astrocyte Regulation of Synaptic Plasticity Balances Robustness and Flexibility of Cell Assemblies
Authors: Koshkin Roman , Fukai Tomoki
Published: August 2024

Cell assemblies are believed to represent the substrate of memory. Although long-term plasticity likely enables the formation of cell assemblies, how other factors, such as astrocytes and short-term plasticity (STP), affect their properties is poorly understood. To close this gap, we investigated cell assembly dynamics in a recurrent network model mimicking the hippocampal area CA3. As shown in experiment, recurrent connections in our model obey a symmetric spike-timing-dependent plasticity (STDP), in which weight change may or may not depend on the releasable amount of neurotransmitter. The former case involves an interplay between STDP and STP. In addition, we implicitly modeled the effect of astrocyte NMDA receptors by manipulating the breadth of the distribution of neurotransmitter release probability in STP. Both STP-dependent and STP-independent STDP enabled spontaneous cell assembly formation. Under the former, however, cell assemblies tend to be smaller and more responsive to external stimulation, improving the network’s memory capacity and enabling flexible network restructuring. Furthermore, astrocyte regulation of the STP-dependent STDP facilitates stimulus-driven reorganization of neural networks without destroying existing assembly structure, thus balancing cell assemblies’ flexibility and robustness. Our findings elucidate the computational advantages of interaction between STP and STDP and highlight astrocytes’ possible regulatory role in memory formation.
Plasmid-chromosome transcriptional crosstalk in multidrug resistant clinical enterobacteria
Authors: Toribio-Celestino Laura , Calvo-Villamañán Alicia , Herencias Cristina , Valle Aida Alonso-del , Sastre-Dominguez Jorge , Quesada Susana , Mazel Didier , Rocha Eduardo PC , Fernández-Calvet Ariadna , San Millan Alvaro
Published: August 2024

Conjugative plasmids promote the dissemination and evolution of antimicrobial resistance in bacterial pathogens. However, plasmid acquisition can produce physiological alterations in the bacterial host, leading to potential fitness costs that determine the clinical success of bacteria-plasmid associations. In this study, we used a transcriptomic approach to characterize the interactions between a globally disseminated carbapenem resistance plasmid, pOXA-48, and a diverse collection of multidrug resistant clinical enterobacteria. Although pOXA-48 produced mostly strain-specific transcriptional alterations, it also led to the common overexpression of a small chromosomal operon present inKlebsiellaspp. andCitrobacter freundiistrains. This operon included two genes coding for a pirin and an isochorismatase family proteins (pfpandifp), and showed evidence of horizontal mobilization across Proteobacteria species. Combining genetic engineering, transcriptomics, and CRISPRi gene silencing, we showed that a pOXA-48-encoded LysR regulator is responsible for the plasmid-chromosome crosstalk. Crucially, the operon overexpression produced a fitness benefit in a pOXA-48-carryingK. pneumoniaeclinical strain, suggesting that this crosstalk promotes the dissemination of carbapenem resistance in clinical settings.
Pyruvate from bone marrow mesenchymal stem cells supports myeloma redox homeostasis and anabolism
Authors: Vera-Sigüenza Elías , Escribano-Gonzalez Cristina , Serrano-Gonzalo Irene , Eskla Kattri-Liis , Speakman Charlotte , Huerta-Uribe Alejandro , Vettore Lisa , Rana Himani , Boufersaoui Adam , Vellama Hans , Nashebi Ramin , Cloete Ielyaas , Roberts Jennie , Basu Supratik , Drayson Mark , Bunce Christopher , Pratt Guy , Spill Fabian , Maddocks Oliver D.K. , Tennant Daniel A.
Published: August 2024

Multiple myeloma is an incurable cancer of plasma cells that depends on the bone marrow for its survival. Despite its prevalence, the molecular mechanisms underlying this malignancy remain poorly understood. In this study, we aim to bridge this knowledge gap by elucidating the metabolic interplay between myeloma cells and bone marrow mesenchymal stem cells (BMMSCs). BMMSCs are crucial in supporting myeloma cell metabolism, contributing to their proliferation, survival, and resistance to chemotherapy. Through a combination of mathematical modelling and experimental co-cultures, we demonstrate that pyruvate – the end product of glycolysis – plays a key role in myeloma cell metabolism. Our findings reveal that myeloma cells predominantly rely on the uptake of pyruvate produced by neighbouring BMM-SCs via the plasma membrane proton-linked monocarboxylate transporters MCT-1 and MCT-2 encoded by the Slc16a1 and a2 genes, respectively. Furthermore, we show that pharmacological inhibition of the MCT-1/2, with AZD3965, triggers a cascade of compensatory metabolic responses, disrupting redox balance and significantly reducing the proliferation capacity of co-cultured myeloma cells.
DeepKin: Predicting relatedness from low-coverage genomes and paleogenomes with convolutional neural networks
Authors: Güler Merve N. , Yılmaz Ardan , Katırcıoğlu Büşra , Kantar Sarp , Ünver Tara Ekin , Vural Kıvılcım Başak , Altınışık N. Ezgi , Akbaş Emre , Somel Mehmet
Published: August 2024

DeepKinis a novel tool designed to predict relatedness from genomic data using convolutional neural networks (CNNs). Traditional methods for estimating relatedness often struggle when genomic data is limited, as with paleogenomes and degraded forensic samples.DeepKinaddresses this challenge by leveraging two CNN models trained on simulated genomic data to classify relatedness up to the third-degree and to identify parent-offspring and sibling pairs. Our benchmarking showsDeepKinperforms comparably or better than the widely used toolREADv2.We validatedDeepKinon empirical paleogenomes from two paleological sites, demonstrating its robustness and adaptability across different genetic backgrounds, with accuracy >90% above 10K shared SNPs. By capturing information across genomic segments,DeepKinoffers a new methodological path for relatedness estimation in settings with highly degraded samples, with applications in ancient DNA, as well as forensic and conservation genetics.
Development of an immunoassay for the detection and diagnosis of microbially-influenced corrosion caused by methanogenic Archaea
Authors: Lahme Sven , Mantilla Aguas Jorge
Published: August 2024

Microbially-influenced corrosion (MIC) is a costly problem across several industries. The steadily rising use of advanced molecular biological methods to investigate MIC allowed ever deeper insights in the underlying microbial community structure and function. However, currently available technologies do not allow accurate detection and diagnosis of MIC in the field. Recent discovery of a special hydrogenase in certain corrosive methanogenic Archaea allowed for the development of a first ever MIC biomarker termed heremicH. ThemicHgene encodes the large subunit of a special [NiFe] hydrogenase involved in MIC. Here we describe the development of a recombinant antibody that enable the specific and sensitive detection of the MicH protein in western blot immunoassays. Using a recombinant MicH protein we determined the lower limit of detection per assay to be around 0.3 fg MicH. The immunoassay was able to detect a strong signal for the MicH protein inmicH-positive pure cultures ofMethanobacterium-like. strain IM1 that was cultivated on iron granules, and the signal was over 500 times lower in amicH-negativeMethanococcus maripaludisS2 culture. To further evaluate the ability to differentiate corrosive from non-corrosive microbial communities, we tested ten oil field enrichment cultures that showed a wide range of corrosion rates (0.02 – 0.48 mm/yr). We detected the MicH protein in planktonic (36.5 – 1473.5 pg/mL) and carbon steel biofilm samples (41.0 – 7971.3 pg/cm2) from corrosive methanogenic enrichments (0.17 – 0.48 mm/yr) but did not detect MicH in any of the non-corrosive tests (<0.08 mm/yr) despite methanogenic activity. The results indicate that corrosion was likely caused by methanogenic Archaea expressing a corrosive [NiFe] hydrogenase and that the newly developed MicH-specific immunoassay can detect and monitor their activity. The development of a specific and sensitive immunoassays to detect a MIC biomarker allow corrosion scientists and field practitioners to detect and monitor the activity of corrosive methanogenic Archaea.
Breast cancer cell-derived extracellular vesicles accelerate collagen fibrillogenesis and integrate into the matrix
Authors: Tam Nicky W. , Dimova Rumiana , Cipitria Amaia
Published: August 2024

Extracellular vesicle (EV) and nanoparticle interactions with extracellular matrix (ECM) environments are often studied through a paradigm whereby particles are a passive element whose diffusion and behaviour are subject to the composition and structure of the environment they are in. While EV diffusion and distribution in tissues are indeed governed by matrix interactions, accumulating evidence suggests that EVs contain much of the cellular machinery required for actively remodeling ECM as well. Using rheology and confocal reflectance microscopy to investigate the gelation of collagen I hydrogels formed in the presence of EVs, we show that EVs can play an active role in the formation of new ECM. EVs appear to nucleate new fibrils, recruiting collagen molecules from solution and accelerating their polymerization. Trypsinization of EVs to digest their surface proteins shows that proteins are primarily responsible for this phenomenon. The use of extruded plasma membrane vesicles shows that membrane composition plays an important role in determining final fibril length and matrix structure. EVs also become integrated into the fibril structures that they help form, reminiscent of matrix vesicles foundin situwithin tissues. This represents a plausible way by which EVs are deposited into the extracellular environment, becoming important contextual signaling cues for resident cells. Our data show that EV-matrix interactions are dynamic and reciprocal, contributing to the remodeling of tissue microenvironments.
Ophthalmic acid is a bloodborne metabolite that contributes to age-induced cardiomyocyte hypertrophy
Authors: Mehdipour Melod , Park Sangsoon , Wei Wei , Long Jonathan Z. , Huang Guo N.
Published: August 2024

Cardiac aging involves the development of left ventricular hypertrophy alongside a decline in functional capacity. Here, we use neutral blood exchange to demonstrate that the acute removal of age-accumulated blood factors significantly regresses cardiac hypertrophy in aged mice. The reversal of hypertrophy was not attributed to age-associated hemodynamic effects, implicating a role of blood-derived factors. In addition, the overarching paradigm of systemic aging maintains that the age-related overabundance of plasma proteins are largely responsible for causing pathological phenotypes in tissues. Our results suggest that blood metabolites, not proteins, drive cardiac hypertrophy instead. Upon analyzing serum metabolomics data sets, we identified ophthalmic acid as a circulating metabolite whose levels increase with advanced age. Treatment of adult mouse and neonatal rat cardiomyocytes in culture with ophthalmic acid increased their relative surface areas. This study uncovers a non-protein metabolite that may contribute to cardiomyocyte hypertrophy during aging. Identifying a method to counteract ophthalmic acid’s hypertrophic effects may reveal novel therapeutic opportunities for cardiac rejuvenation.
CD38 mediates nicotinamide mononucleotide (NMN) base exchange to yield nicotinic acid mononucleotide (NaMN)
Authors: Madawala Romanthi , Banks Jasmine L. , Hancock Sarah E. , Quek Lake-Ee , Turner Nigel , Wu Lindsay E.
Published: August 2024

Nicotinamide mononucleotide (NMN) is a widely investigated metabolic precursor to the prominent redox cofactor nicotinamide adenine dinucleotide (NAD+), where it is assumed that delivery of this compound results in its direct incorporation into NAD+via the canonical salvage / recycling pathway. Surprisingly, treatment with this salvage pathway intermediate leads to increases in nicotinic acid mononucleotide (NaMN) and nicotinic acid adenine dinucleotide (NaAD), two members of the Preiss-Handler /de novopathways. In mammals, these pathways are not known to intersect prior to the production of NAD+. Here, we show that the cell surface enzyme CD38 can mediate a base exchange reaction on NMN, whereby the nicotinamide ring is exchanged with a free nicotinic acid to yield the Preiss-Handler /de novopathway intermediate NaMN, within vivosmall molecule inhibition of CD38 abolishing the NMN-induced increase in NaMN and NaAD. Together, these data demonstrate a new mechanism by which the salvage pathway and Preiss-Handler /de novopathways can exchange intermediates in mammalian NAD+biosynthesis.
Synthetic Data Generation in Healthcare: A Scoping Review of reviews on domains, motivations, and future applications
Authors: Rujas Miguel , del Moral Herranz Rodrigo Martín Gómez , Fico Giuseppe , Merino-Barbancho Beatriz
Published: August 2024

The development of Artificial Intelligence (AI) in the healthcare sector is generating a great impact. However, one of the primary challenges for the implementation of this technology is the access to high-quality data due to issues in data collection and regulatory constraints, for which synthetic data is an emerging alternative. This Scoping review analyses reviews from the past 10 years from three different databases (i.e., PubMed, Scopus, and Web of Science) to identify the healthcare domains where synthetic data are currently generated, the motivations behind their creation, their future uses, limitations, and types of data. A total of 13 main domains were identified, with Oncology, Neurology, and Cardiology being the most frequently mentioned. Five types of motivations and three principal future uses were also identified. Furthermore, it was found that the predominant type of data generated is unstructured, particularly images. Finally, several future work directions were suggested, including exploring new domains and less commonly used data types (e.g., video and text), and developing an evaluation benchmark and standard generative models for specific domains.
Commuting-driven competition between transmission chains shapes seasonal influenza virus epidemics in the United States
Authors: de Jong Simon P.J. , Conlan Andrew , Han Alvin X. , Russell Colin A.
Published: August 2024

Despite intensive study, much remains unknown about the dynamics of seasonal influenza virus epidemic establishment and spread in the United States (US) each season. By reconstructing transmission lineages from seasonal influenza virus genomes collected in the US from 2014 to 2023, we show that most epidemics consisted of multiple distinct transmission lineages. Spread of these lineages exhibited strong spatiotemporal hierarchies and lineage size was correlated with timing of lineage establishment in the US. Mechanistic epidemic simulations suggest that mobility-driven competition between lineages determined the extent of individual lineages’ geographical spread. Based on phylogeographic analyses and epidemic simulations, lineage-specific movement patterns were dominated by human commuting behavior. These results suggest that given the locations of early-season epidemic sparks, the topology of inter-state human mobility yields repeatable patterns of which influenza viruses will circulate where, but the importance of short-term processes limits predictability of regional and national epidemics.

Teaser

Epidemics consist of multiple sub-epidemics that compete for susceptible hosts and spread due to the movement of commuters.
ZO-1 shuttles between tight junctions and podosomes by riding ERK activation waves during collective cell migration
Authors: Hirano Sayuki , Kondo Yohei , Kinoshita Noriyuki , Otani Tetsuhisa , Furuse Mikio , Ueno Naoto , Aoki Kazuhiro
Published: August 2024

Collective cell migration is essential in various physiological processes, including embryonic development, wound healing, and cancer metastasis. However, the mechanisms by which individual cells achieve coordinated movement remain elusive. Here, we demonstrate that zonula occludens-1 (ZO-1), a scaffolding protein of tight junctions (TJs), dynamically translocates to form cell-to-extracellular matrix (ECM) adhesion complexes, podosomes, at the basal cell surface during migration. The translocation of ZO-1 is regulated by extracellular signal-regulated kinase (ERK) activity and its interaction with F-actin. ZO-1 at podosomes contributes to traction force generation and cell invasion, while ZO-1 at TJs mediates intercellular propagation of ERK activation, facilitating collective cell migration. These findings elucidate the versatile roles of ZO-1 in cell adhesion and movement, providing insights into the mechanisms coordinating the discrete movements of individual cells into a cohesive and directed collective cell migration.
Systemic metabolic changes in acute and chronic lymphocytic choriomeningitis virus infection
Authors: Bartman Caroline , Hou Shengqi , Correa Fabian , Shen Yihui , da Silva-Diz Victoria , Aleksandrova Maya , Herranz Daniel , Rabinowitz Josh , Intlekofer Andrew
Published: August 2024

Viral infection of cells leads to metabolic changes, but how viral infection changes whole-body and tissue metabolismin vivohas not been comprehensively studied. In particular, it is unknown how metabolism might be differentially affected by an acute infection that the immune system can successfully clear, compared to a chronic and persistent infection. Here we used metabolomics and isotope tracing to identify metabolic changes in mice infected with acute or chronic forms of lymphocytic choriomeningitis virus (LCMV) for three or eight days. Both types of infection alter metabolite levels in blood and tissues, including itaconate and thymidine. However, we observed more dramatic metabolite changes in the blood and tissues of mice with chronic LCMV infection compared to those with acute infection. Isotope tracing revealed that the contribution of both glucose and glutamine to the tricarboxylic acid (TCA) cycle increase in the spleen, liver, and kidneys of mice infected with chronic LCMV, while acute LCMV only increases the contribution of glutamine to the TCA cycle in the spleen. We found that whole-body turnover of both glutamine and thymidine increase during acute and chronic infection, whereas whole-body glucose turnover was surprisingly unchanged. Activated T cellsin vitroproduce thymidine and mice with T cell leukemia display elevated serum thymidine, nominating T lymphocytes as the source of thymidine in LCMV infection. In sum, we provide comprehensive measurements of whole-body and tissue metabolism in acute and chronic viral infection, and identify altered thymidine metabolism as a marker of viral infection.
Coupling renormalization flow in the strongly interacting regime of an asymptotically free quantum field theory in four dimensions
Authors: Berges Jürgen , Gurau Razvan , Keppler Hannes , Preis Thimo
Published: August 2024

We consider a scalar quantum field theory with global O(N)3 symmetry in four Euclidean dimensions and solve it numerically in closed form in the large-N limit. For imaginary tetrahedral coupling the theory is asymptotically free, with stable and real quantum effective action. We demonstrate the dynamical build-up of a strong interaction as the correlation length increases in a regime where the coupling renormalization flow remains well defined in the infrared. This is in contrast to perturbative results of asymptotically free theories, which predict that the coupling becomes ill defined in the infrared, like in quantum chromodynamics. These properties make the model an important laboratory for the study of strong-coupling phenomena in quantum field theory from first principles.

Published by the American Physical Society
2024
Exploring critical behavior of thermodynamic variables of the Kerr-Newman-AdS black hole in the restricted phase space
Authors: Tripathy Pabitra
Published: August 2024

The present work investigates the thermodynamic properties of the four-dimensional Kerr-Newmann-AdS black hole, utilizing the recently proposed framework of restricted phase space thermodynamics. This approach introduces a novel set of paired thermodynamic variables; the central charge (C) of the corresponding dual conformal field theory and the chemical potential (μ). Through rigorous analysis, we establish fundamental relationships, including the Euler relation, Gibbs-Duhem relation, and the zeroth-order homogeneity of intensive variables. Furthermore, numerical techniques are employed to explore thermodynamic processes between the conjugate variables in canonical and grand canonical ensembles. Our investigation reveals first-order and second-order phase transitions across various macroscopic processes. Despite the absence of complete analytical expressions, our findings unveil striking similarities in behavior between Reissner-Nordström-Anti-de Sitter and Kerr-anti–de Sitter, underscoring the presence of underlying universality within the restricted phase space thermodynamics formalism.

Published by the American Physical Society
2024
First order phase transition with the functional renormalization group method
Authors: Nagy S. , Polonyi J.
Published: August 2024

The renormalization group method, more specifically the Wegner-Houghton equation, is used to find first order phase transitions in a simple scalar field theory with a polynomial potential. An improved definition of the running parameters allows us to explore the renormalization group flow down to the IR endpoint and to locate phase transitions. Beyond the expected first order transition further radiative correction generated first and second order transitions are found. The phase diagram is reviewed by a Monte-Carlo simulation of the lattice regulated version of the theory but the serious slow down of the convergence prevents us from obtaining conclusive results from the simulation.

Published by the American Physical Society
2024
Holographic entanglement properties in the QCD phase diagram from Einstein-Maxwell-dilaton models
Authors: Li Zhibin
Published: August 2024

In this study, we investigate the behavior of entanglement properties in the QCD phase diagram using holographic Einstein-Maxwell-dilaton models. We consider two representative holographic QCD models and examine various entanglement measures, including entanglement entropy, conditional mutual information, and the entanglement of purification. We find that the entanglement entropy obtained using the direct UV-cutoff renormalization method shows significant dependence on the specific model being used. However, the outcomes of other nondivergent entanglement measures, such as cutoff-independent entanglement entropy, conditional mutual information, and the entanglement of purification, exhibit congruence in our calculations. When we focus specifically on the temperature range below 300 MeV, we observe a similar behavior among the three entanglement measures. This may suggest that within this temperature range, the entanglement of QCD matter decreases with increasing temperature. Additionally, we observe distinct phase transition behaviors of entanglement properties at the critical end point and first-order phase transitions. This observation highlights the potential of entanglement properties as effective order parameters for QCD matter phase transitions.

Published by the American Physical Society
2024