bluuebunny/crossref_metadata_2025 huggingface dataset:
Approximate Bayesian computation for inferring Waddington landscapes from single-cell data
Authors: Liu Yujing , Zhang Stephen Y. , Kleijn Istvan T. , Stumpf Michael P. H.
Published: July 2024

Single-cell technologies allow us to gain insights into cellular processes at unprecedented resolution. In stem cell and developmental biology snapshot data allow us to characterize how the transcriptional states of cells change between successive cell types. Here, we show how approximate Bayesian computation (ABC) can be employed to calibrate mathematical models against single-cell data. In our simulation study, we demonstrate the pivotal role of the adequate choice of distance measures appropriate for single-cell data. We show that for good distance measures, notably optimal transport with the Sinkhorn divergence, we can infer parameters for mathematical models from simulated single-cell data. We show that the ABC posteriors can be used (i) to characterize parameter sensitivity and identify dependencies between different parameters and (ii) to construct representations of the Waddington or epigenetic landscape, which forms a popular and interpretable representation of the developmental dynamics. In summary, these results pave the way for fitting mechanistic models of stem cell differentiation to single-cell data.
Metagenomic profiling of nasopharyngeal samples from adults with acute respiratory infection
Authors: Sandybayev Nurlan , Beloussov Vyacheslav , Strochkov Vitaliy , Solomadin Maxim , Granica Joanna , Yegorov Sergey
Published: July 2024

Diagnosis of acute respiratory infections (ARIs) is challenging due to the broad diversity of potential microbial causes. We used metagenomic next-generation sequencing (mNGS) to analyze the nasopharyngeal virome of ARI patients, who had undergone testing with a clinical multiplex PCR panel (Amplisens ARVI-screen-FRT). We collected nasopharyngeal swabs from 49 outpatient adults, 32 of whom had ARI symptoms and were PCR-positive, and 4 asymptomatic controls in Kazakhstan during Spring 2021. We assessed the biodiversity of the mNGS-derived virome and concordance with PCR results. PCR identified common ARI viruses in 65% of the symptomatic cases. mNGS revealed viral taxa consisting of human, non-human eukaryotic and bacteriophage groups, comprising 15, 11 and 28 genera, respectively. Notable ARI-associated human viruses included rhinovirus (16.3%), betaherpesvirus 7 (14.3%) and Epstein-Barr virus (8.16%). The primary phage hosts were
Streptococcus
spp. (32.7%),
Pseudomonas aeruginosa
(24.5%) and
Burkholderia
spp. (20.4%). In total, 47% of ARIs were linked solely to bacterial pathogens, a third to viral-bacterial co-infections, and less than 10% to only viral infections by mNGS. PCR showed low concordance with mNGS, except for rhinovirus. These results underscore the importance of broad diagnostic methods and question the effectiveness of commonly used PCR panels in ARI diagnosis.
Origins of mammalian vertebral function revealed through digital bending experiments
Authors: Jones Katrina E. , Angielczyk Kenneth D. , Pierce Stephanie E.
Published: July 2024

Unravelling the functional steps that underlie major transitions in the fossil record is a significant challenge for biologists owing to the difficulties of interpreting functional capabilities of extinct organisms. New computational modelling approaches provide exciting avenues for testing function in the fossil record. Here, we conduct digital bending experiments to reconstruct vertebral function in non-mammalian synapsids, the extinct forerunners of mammals, to provide insights into the functional underpinnings of the synapsid–mammal transition. We estimate range of motion and stiffness of intervertebral joints in eight non-mammalian synapsid species alongside a comparative sample of extant tetrapods, including salamanders, reptiles and mammals. We show that several key aspects of mammalian vertebral function evolved outside crown Mammalia. Compared to early diverging non-mammalian synapsids, cynodonts stabilized the posterior trunk against lateroflexion, while evolving axial rotation in the anterior trunk. This was later accompanied by posterior sagittal bending in crown mammals, and perhaps even therians specifically. Our data also support the prior hypothesis that functional diversification of the mammalian trunk occurred via co-option of existing morphological regions in response to changing selective demands. Thus, multiple functional and evolutionary steps underlie the origin of remarkable complexity in the mammalian backbone.
Longer days, larger grays: carryover effects of photoperiod and temperature in gray treefrogs,
Hyla versicolor
Authors: Neptune Troy C. , Benard Michael F.
Published: July 2024

Environmental conditions like temperature and photoperiod can strongly shape organisms’ growth and development. For many ectotherms with complex life cycles, global change will cause their offspring to experience warmer conditions and earlier-season photoperiods, two variables that can induce conflicting responses. We experimentally manipulated photoperiod and temperature during gray treefrog (
Hyla versicolor
) larval development to examine effects at metamorphosis and during short (10-day) and long (56-day) periods post-metamorphosis. Both early- and late-season photoperiods (April and August) decreased age and size at metamorphosis relative to the average-season (June) photoperiod, while warmer temperatures decreased age but increased size at metamorphosis. Warmer larval temperatures reduced short-term juvenile growth but had no long-term effect. Conversely, photoperiod had no short-term carryover effect, but juveniles from early- and late-season larval photoperiods had lower long-term growth rates than juveniles from the average-season photoperiod. Similar responses to early- and late-season photoperiods may be due to reduced total daylight compared with average-season photoperiods. However, juveniles from late-season photoperiods selected cooler temperatures than early-season juveniles, suggesting that not all effects of photoperiod were due to total light exposure. Our results indicate that despite both temperature and photoperiod affecting metamorphosis, the long-term effects of photoperiod may be much stronger than those of temperature.
Engineering of Transmembrane Alkane Monooxygenases to Improve a Key Reaction Step in the Synthesis of Polymer Precursor Tulipalin A
Authors: Nigl Andrea , Delsoglio Veronica , Grgić Marina , Malihan-Yap Lenny , Myrtollari Kamela , Spasic Jelena , Winkler Margit , Oberdorfer Gustav , Taden Andreas , Anić Iva , Kourist Robert
Published: July 2024

The α-methylene-γ-butyrolactone tulipalin A, naturally found in tulips can polymerize via addition at the vinyl group or via ring-opening polymerization, making it a highly promising monomer for biobased polymers. As tulipalin A biosynthesis in plants remains elusive, we propose a pathway for its synthesis starting from the metabolic intermediate isoprenol. For this, terminal hydroxylation of the α-methylene substrate isoprenyl acetate is a decisive step. While a panel of fungal unspecific peroxygenases showed a preference for the undesired epoxidation of theexo-olefin group, bacterial alkane monooxygenases were specific for terminal hydroxylation. A combination of protein engineering based onde novostructure prediction of the membrane enzymes with cell engineering allowed to increase the specific activity by 6-fold to 1.83 U gcdw-1, unlocking this reaction for the fermentative production of tulipalin A from renewable resources.
Chronic inorganic nitrate supplementation does not improve metabolic health and worsens disease progression in mice with diet-induced obesity
Authors: Sowton Alice P. , Holzner Lorenz M.W. , Krause Fynn N. , Baxter Ruby , Mocciaro Gabriele , Krzyzanska Dominika K. , Minnion Magdalena , O’Brien Katie A. , Harrop Matthew C. , Darwin Paula M. , Thackray Benjamin D. , Vacca Michele , Feelisch Martin , Griffin Julian L. , Murray Andrew J.
Published: July 2024

Inorganic nitrate (NO3-) has been proposed to be of therapeutic use as a dietary supplement in obesity and related conditions including the Metabolic Syndrome (MetS), type-II diabetes and metabolic dysfunction associated steatotic liver disease (MASLD). Administration of NO3-to endothelial nitric oxide synthase-deficient mice reversed aspects of MetS, however the impact of NO3-supplementation in diet-induced obesity is not well understood. Here we investigated the whole-body metabolic phenotype and cardiac and hepatic metabolism in mice fed a high-fat high-sucrose (HFHS) diet for up to 12-months of age, supplemented with 1 mM NaNO3(or NaCl) in their drinking water. HFHS-feeding was associated with a progressive obesogenic and diabetogenic phenotype, which was not ameliorated by NO3-. Furthermore, HFHS-fed mice supplemented with NO3-showed elevated levels of cardiac fibrosis, and accelerated progression of MASLD including development of hepatocellular carcinoma in comparison with NaCl-supplemented mice. NO3-did not enhance mitochondrial β-oxidation capacity in any tissue assayed and did not suppress hepatic lipid accumulation, suggesting it does not prevent lipotoxicity. We conclude that NO3-is ineffective in preventing the metabolic consequences of an obesogenic diet and may instead be detrimental to metabolic health against the background of HFHS-feeding. This is the first report of an unfavorable effect of long-term nitrate supplementation in the context of the metabolic challenges of overfeeding, warranting urgent further investigation into the mechanism of this interaction.

New & Noteworthy

Inorganic nitrate has been suggested to be of therapeutic benefit in obesity-related conditions as it increases nitric oxide bioavailability, enhances mitochondrial β-oxidation and reverses Metabolic Syndrome ineNOS-/-mice. However, we here show that over 12 months, nitrate was ineffective in preventing metabolic consequences in high-fat high-sucrose fed mice, and worsened aspects of metabolic health, impairing cholesterol handling, increasing cardiac fibrosis, and exacerbating steatotic liver disease progression, with acceleration to hepatocellular carcinoma.
Unraveling the Link between Nutrition and Metabolic Syndrome Risk through In Silico Dietary Interventions
Authors: Alessi Drew , McCreery Chloe , Zomorrodi Ali R.
Published: July 2024

Metabolic Syndrome (MetS) is a cluster of metabolic disorders that substantially increases the risk of chronic metabolic diseases. Diet is known to play a crucial role in the progression of MetS, yet a mechanistic understanding of its impact on MetS risk remains elusive. To address this gap, we conducted a rigorous in silico diet intervention study by leveraging organ-resolved sex-specific whole-body models (WBMs) of metabolism. These models were utilized to computationally evaluate the effect of 12 diverse dietary regimens on key MetS biomarkers—glucose, triacylglycerides (TAG), LDL-C, and HDL-C—and fatty acid beta-oxidation in both males and females. Our analyses elucidated molecular mechanisms underlying the link between conventionally unhealthy diets and elevated MetS risk. Specifically, a typical Unhealthy or Keto diet indicated elevated TAG storage in the adipocytes and increased LDL-C to HDL-C ratios across both genders. Conversely, healthier dietary patterns like the Mediterranean and Vegan diets promoted favorable metabolic profiles, characterized by lower TAG storage and LDL-C to HDL-C ratios. Notably, plant-based (Vegan and Vegetarian) diets induced elevated fatty acid oxidation compared to high-fat regimens, suggesting their potential in mitigating MetS risk. Pronounced gender differences in metabolic responses to diets were also observed in our analyses, highlighting the need for gender-tailored dietary recommendations. Additionally, our study delineated organ-specific contributions to the MetS biomarkers, with the liver and lungs identified as major regulators of blood glucose homeostasis. Overall, this study contributes to a deeper understanding of the intricate interactions between diet and MetS risk.
The dynamic gene regulatory landscape of the mouse brain in response to sleep deprivation
Authors: Bafna Akanksha , Dang Quang , Taylor Lewis , Walsh Steven , Sims David , George Charlotte , Jagannath Aarti
Published: July 2024

Sleep deprivation (SD) negatively impacts nearly all brain functions including cognition, memory consolidation and metabolism. However, the gene regulatory networks that underlie these biological effects are not well understood. In order to identify these networks, we conducted a multiomic analysis to analyse how gene expression, chromatin accessibility, enhancer activity and DNA methylation change with acute SD in mice. By studying three brain regions involved in different aspects of sleep - the cortex (CTX), dentate gyrus (DG), and suprachiasmatic nucleus (SCN) - we found that the effects of SD on the multiome varied widely, impacting physiological processes specific to each area, from spine formation in the dentate gyrus to neuropeptide release in the SCN. Our integrated analysis showed that distinct brain region-specific networks of regulatory factors dynamically alter the epigenomic landscape in response to SD to orchestrate transcriptional responses. These findings provide new understanding of the regulatory grammar encoded within the genome, which enables a general physiological signal like SD to produce unique effects in a tissue-specific context.
Infrared thermography for plant stress detection in vertical farms: Investigating spatiotemporal variations and exploring solutions via machine learning
Authors: Agarwal Avinash , de Jesus Colwell Filipe , Dinnis Rosalind , Correa Galvis Viviana Andrea , Hill Tom , Boonham Neil , Prashar Ankush
Published: July 2024

Application of infrared thermography (IRT) for real-time plant stress detection has grown rapidly in recent years. Although the technology has been well established for crops grown in fields and glasshouses, its feasibility for vertical farms has not been tested extensively. In this study, temporal monitoring of stress induced by root dehydration in purple basil plantlets inside a vertical farm was performed to identify bottlenecks in real-time stress detection via IRT. Subsequently, potential solutions were investigated via machine learning by implementing support vector machines for supervised classification. Edge effects as well as proximity to air vents were identified as the major causes of positional variation in plant temperature that could lead to misprediction of stress. Binary, ternary, and quaternary classification models were trained using thermal images from two, three, and four levels of stress, respectively, to assess model performance. Binary classification models trained with plants experiencing medial and high levels of stress were able to identify stressed plants with high accuracy (81–94%). Further, binary models trained using plants under medial levels of stress generated a continuous probability distribution for stress prediction when plotted against plant temperature. In contrast, models trained using samples experiencing high stress generated distinct probabilistic clusters for the unstressed and highly stressed plants, but were unable to classify medial stress samples reliably. Similarly, ternary and quaternary models were able to better predict very high and very low levels of stress than intermediate stress levels. Hence, our findings suggest that binary classification models trained using samples under medial levels of stress would be helpful in overcoming spatiotemporal variations in canopy thermal profile by providing reliable probabilistic estimates of plant stress within a vertical farming system.

Key points

Plant stress detection in vertical farms via thermal imaging may be challenging because perceptible plant temperature can be strongly influenced by its microenvironment.

Thermal image analysis via supervised machine learning allows the development of robust prediction models that can overcome such factors to identify stressed plants.

Binary classification machine learning models can reliably identify stressed plants as well as provide probabilistic estimates for the degree of stress.
Antimicrobial cetylpyridinium chloride suppresses mast cell function by targeting tyrosine phosphorylation of Syk kinase
Authors: Obeng Bright , Bennett Lucas J. , West Bailey E. , Wagner Dylan J. , Fleming Patrick J. , Tasker Morgan N. , Lorenger Madeleine K. , Smith Dorothy R. , Systuk Tetiana , Plummer Sydni M. , Eom Jeongwon , Paine Marissa D. , Frangos Collin T. , Wilczek Michael P. , Shim Juyoung K. , Maginnis Melissa S. , Gosse Julie A.
Published: July 2024

Cetylpyridinium chloride (CPC) is a quaternary ammonium antimicrobial used in numerous personal care products, human food, cosmetic products, and cleaning solutions. Yet, there is minimal published data on CPC effects on eukaryotes, immune signaling, and human health. Previously, we showed that low-micromolar CPC inhibits rat mast cell function by inhibiting antigen (Ag)-stimulated Ca2+mobilization, microtubule polymerization, and degranulation. In this study, we extend the findings to human mast cells (LAD2) and present data indicating that CPC’s mechanism of action centers on its positively-charged quaternary nitrogen in its pyridinium headgroup. CPC’s inhibitory effect is independent of signaling platform receptor architecture. Tyrosine phosphorylation events are a trigger of Ca2+mobilization necessary for degranulation. CPC inhibits global tyrosine phosphorylation in Ag-stimulated mast cells. Specifically, CPC inhibits tyrosine phosphorylation of specific key players Syk kinase and LAT, a substrate of Syk. In contrast, CPC does not affect Lyn kinase phosphorylation. Thus, CPC’s root mechanism is electrostatic disruption of particular tyrosine phosphorylation events essential for signaling. This work outlines the biochemical mechanisms underlying the effects of CPC on immune signaling and allows the prediction of CPC effects on cell types, like T cells, that share similar signaling elements.
Thickness and quality controlled fabrication of fluorescence-targeted frozen-hydrated lamellae
Authors: Boltje Daan B. , Skoupy Radim , Taisne Clémence , Evers Wiel H. , Jakobi Arjen J. , Hoogenboom Jacob P.
Published: July 2024

Cryogenic focused ion beam (FIB) milling is essential for fabricating thin lamella-shaped samples out of frozen-hydrated cells for high-resolution structure determination. Structural information can only be resolved at high resolution if the lamella thickness is between 100 and 200 nm. While the lamella fabrication workflow has undergone significant improvements since its conception, quantitative, live feedback on lamella thickness and quality is still lacking. Taking advantage of a coincident light microscopy integrated into the FIB-SEM, we present three different strategies that together allow accurate, live control during lamella fabrication. First, we combine 4D-STEM with fluorescence microscope (FM) targeting to determine the lamella thickness. Second, with reflected light microscopy (RLM) we screen target sites for ice contamination and monitor lamella thickness and integrity of the protective Pt coating during FIB milling. Third, we exploit thin-film interference to obtain fine-grained feedback on thickness uniformity below 500 nm. We finally present a full workflow for fluorescence-targeted and quality controlled fabrication of frozen-hydrated lamellae, benchmarked with excellent agreement to energy filtered transmision electron microscopy (EFTEM) measurements and reconstructed tomograms obtained with electron cryo-tomography.
A Systematic Review of the Distribution and Prevalence of Viruses Detected in thePeromyscus maniculatusSpecies Complex (Rodentia: Cricetidae)
Authors: Finkbeiner Ally , Khatib Ahmad , Upham Nathan , Sterner Beckett
Published: July 2024

The North American Deermouse,Peromyscus maniculatus, is one of the most widespread and abundant mammals on the continent. It is of public health interest as a known host of several viruses that are transmissible to humans and can cause illness, including the acute respiratory disease Hantavirus pulmonary syndrome (HPS). However, recent taxonomic studies indicate thatP. maniculatusis a complex of multiple species, raising questions about how to identify and interpret three decades of hantavirus monitoring data. We conducted a systematic review investigating the prevalence and spatial distribution of viral taxa detected in wild populations allocated toP. maniculatus. From the 49 relevant studies published from 2000 to 2022, we extracted and analyzed spatial occurrence data to calculate weighted populational prevalences for hantaviruses. We found that detection efforts have been concentrated in the Western United States and Mexico with a focus on the spread of Sin Nombre virus (Orthohantavirus sinnombreense), the primary causative agent of HPS. There are significant gaps in the existing literature both geographically and in regard to the types of viruses being sampled. These results are significantly impacted by a recent taxonomic split ofP. maniculatusinto four species, and we were able to update 94% of hantavirus observations to reflect this change. Investigating the uncertain, and likely multiple, phylogenetic histories of these viral hosts should be a key emphasis of future modeling efforts.

Author Summary

Understanding the interactions of viruses with mammal hosts is critical for monitoring disease spread and identifying species or geographic areas at high risk for future zoonotic disease outbreaks. However, much of the data scientists have collected about viruses in mammals remains fragmented in published literature and is not available in an up-to-date, standardized format online. We conducted a systematic review of virus observations in one of the most abundant, widespread group of rodent species in North America, thePeromyscus maniculatus(North American Deermouse) species complex. We extracted and analyzed the spatial distribution of 62,421 observations reporting the results of tests for viruses in the Hantaviridae, Arenaviridae, and Flaviviridae families. We find that conclusions about reservoir host status may be impacted by recent taxonomic proposals that splitP. maniculatusinto four distinct species, and we show how the taxonomic identifications of 94% of the reported observations can be updated using expert-generated maps of the ranges for the proposed new species. We also highlight the uneven geographic sampling of viruses in the rodent populations and major gaps that remain in our knowledge.
Heli-SMACC: Helicase-targeting SMAll Molecule Compound Collection
Authors: Martin Holli-Joi , Hossain Mohammad A. , Wellnitz James , Kelestemur Enes , Hochuli Joshua E. , Parveen Sumera , Arrowsmith Cheryl , Willson Timothy M. , Muratov Eugene , Tropsha Alexander
Published: July 2024

Helicases have emerged as promising targets for the development of antiviral drugs; however, the family remains largely undrugged. To support the focused development of viral helicase inhibitors we identified, collected, and integrated all chemogenomics data for all available helicases from the ChEMBL database. After thoroughly curating and enriching the data with relevant annotations we have created a derivative database of helicase inhibitors which we dubbed Heli-SMACC (Helicase-targetingSMAll MoleculeCompoundCollection). The current version of Heli-SMACC contains 20,432 bioactivity entries for viral, human, and bacterial helicases. We have selected 30 compounds with promising viral helicase activity and tested them in a SARS-CoV-2 NSP13 ATPase assay. Twelve compounds demonstrated ATPase inhibition and a consistent dose-response curve. The Heli-SMACC database may serve as a reference for virologists and medicinal chemists working on the development of novel helicase inhibitors. Heli-SMACC is publicly available athttps://smacc.mml.unc.edu.

Highlights

We created a curated Helicase-Targeting SMAll Molecule Compound Collection (Heli-SMACC).

Heli-SMACC covers 29 human, viral, and bacterial helicases.

Twelve of thirty selected compounds demonstrated inhibitory activity in a SARS-CoV-2 NSP13 ATPase Assay.

Heli-SMACC is freely available online athttps://smacc.mml.unc.edu.

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LAG-3 blockade reactivates the CD8+T cell expansion program to re-expand contracted clones in the tumor
Authors: Takahashi Munetomo , Tsunoda Mikiya , Aoki Hiroyasu , Kurosu Masaki , Ogiwara Haru , Shichino Shigeyuki , Bending David , Ishikawa Shumpei , Thaventhiran James E.D. , Matsushima Kouji , Ueha Satoshi
Published: July 2024

Effective cancer immunotherapy relies on the clonal proliferation and expansion of CD8+T cells in the tumor1,2. However, our insights into clonal expansions are limited, owing to an inability to track the same clones in tumors over time. Here, we developed a multi-tumor mouse model system to track hundreds of expanding and contracting CD8+T cell clones over multiple timepoints in tumors of the same individual. Through coupling of clonal expansion dynamics and single-cell RNA/TCR-seq data, we identified a transcriptomic signature in PD-1+Ly108+precursor exhausted cells3,4that strongly predicts rates of intratumoral clone expansion in mice and humans. We found that expression of the signature successfully stratifies melanoma patient outcomes to PD-1/PD-L1 blockade5,6. Downregulation of the signature precedes clone contraction – a phase in which clones contract but maintain revivable precursor exhausted cells in the tumor. LAG-3 blockade – an FDA-approved therapy whose effects on CD8+T cell responses are currently unclear7, re-activates the expansion signature, re-expanding pre-existing clones, including previously contracted clones. These findings reveal how the study of clonal expansion dynamics provide a powerful ‘pan-immunotherapy’ signature for monitoring immunotherapies, including PD-1/PD-L1 and LAG-3 blockade, with implications for their future development.
Deterministic processes played more important roles than stochastic processes in driving community assembly of ectomycorrhizal fungal associated withPinus tabuliformis –an endemic Pinaceae species in China
Authors: Fan Yongjun , Yu Zhimin , Li Jinyan , Zhang Xuan , Li Min , Ma Jianjun , Wang Yonglong
Published: July 2024

Pinus tabuliformisrepresents a typical and essential woody ectomycorrhizae (EM) host plant growing in North China. EM fungi contribute to the host healthy and the stability of the forest ecosystem. However, EM fungal community associated with this tree is less documented. We examined EM fungal diversity and composition ofP. tabuliformisfrom three sites in Inner Mongolia, China by using Illumina MiSeq sequencing on the rDNA ITS2 region. Our results showed that a total of 105 EM fungal operational taxonomic units (OTUs) were identified from 15 composite root samples, and the dominant lineages were /suillus-rhizopogon, /tomentella-thelephora, /tricholoma, /amphinema-tylospora, /wilcoxina, /inocybeand /Sebacina. A high proportion of unique EM fungal OTUs were detected and some abundant OTUs preferred to exist in specific sites. EM fungal communities were significantly different among the sites, with soil, climatic and spatial variables being responsible for the community variations. The EM fungal community assembly was mainly governed by deterministic processes. These findings suggest that this endemic Pinaceae species in China also harbored a rich and distinctive EM fungal community and deterministic processes played more important roles than stochastic in shaping the symbiotic fungal community. Our study improves our understanding of EM fungal diversity and community structure from the perspective of a single host plant that has not been investigated exclusively before.
VirID: Beyond Virus Discovery - An Integrated Platform for Comprehensive RNA Virus Characterization
Authors: Yang Ziyue , Shan Yongtao , Liu Xue , Chen Guowei , Pan Yuanfei , Gou Qinyu , Zou Jie , Chang Zilong , Zeng Qiang , Yang Chunhui , Kong Jianbin , Sun Yanni , Li Shaochuan , Zhang Xu , Wu Wei Chen , Li Chunmei , Peng Hong , Holmes Edward C. , Guo Deyin , Shi Mang
Published: July 2024

RNA viruses exhibit vast phylogenetic diversity and can significantly impact public health and agriculture. However, current bioinformatics tools for viral discovery from metagenomic data frequently generate false positive virus results, overestimate viral diversity, and misclassify virus sequences. Additionally, current tools often fail to determine virus-host associations, which hampers investigation of the potential threat posed by a newly detected virus. To address these issues we developed VirID, a software tool specifically designed for the discovery and characterization of RNA viruses from metagenomic data. The basis of VirID is a comprehensive RNA-dependent RNA polymerase (RdRP) database to enhance a workflow that includes RNA virus discovery, phylogenetic analysis, and phylogeny-based virus characterization. Benchmark tests on a simulated data set demonstrated that VirID had high accuracy in profiling viruses and estimating viral richness. In evaluations with real-world samples, VirID was able to identity RNA viruses of all type, but also provided accurate estimations of viral genetic diversity and virus classification, as well as comprehensive insights into virus associations with humans, animals, and plants. VirID therefore offers a robust tool for virus discovery and serves as a valuable resource in basic virological studies, pathogen surveillance, and early warning systems for infectious disease outbreaks.
Drivers of recovery and degradation of riverine benthic macroinvertebrate communities: A nationwide analysis of time series
Authors: Schürings Christian , Kaijser Willem , Gillmann Svenja , Peters Kristin , Kiesel Jens , Lorenz Armin W. , Hering Daniel
Published: July 2024

In response to the global freshwater biodiversity crisis this study examines the drivers, influencing recovery and degradation in riverine benthic macroinvertebrate communities across Germany. Utilizing the Asymmetric Response Concept (ARC), which posits that species tolerances to stressors, dispersal capacity, and biotic interactions are critical drivers in aquatic ecosystem recovery, we analyzed a comprehensive dataset from 1568 sites, sampled between 2004 and 2022. Our findings indicate that abiotic stress consistently influences ecological status in both recovery and degradation phases. Interspecific competition shows a stronger positive relationship with ecological status improvements during recovery phases than during degradation, underscoring its importance in the recovery process. Additionally, land use intensity has a nuanced impact: catchments with higher proportions of cropland and urban areas are more likely to recover, while forested catchments are more prone to degradation. This study supports the ARC and highlights the complex interplay of biotic and abiotic variables in shaping ecological outcomes, underscoring the importance of integrated management approaches in freshwater conservation and restoration efforts.
Reconstructing the phylogeny and evolutionary history of freshwater fishes (Nemacheilidae) across Eurasia since early Eocene
Authors: Šlechtová Vendula , Dvořák Tomáš , Freyhof Jörg , Kottelat Maurice , Levin Boris , Golubtsov Alexander , Šlechta Vlastimil , Bohlen Jörg
Published: July 2024

Eurasia has undergone substantial tectonic, geological, and climatic changes throughout the Cenozoic era, primarily associated with tectonic plate collisions and a global cooling trend. The evolution of present-day biodiversity unfolded in this dynamic environment, characterised by intricate interactions of abiotic factors. However, comprehensive, large-scale reconstructions illustrating the extent of these influences are lacking. We reconstructed the evolutionary history of the freshwater fish family Nemacheilidae across Eurasia and spanning most of the Cenozoic era on the base of 471 specimens representing 279 species and 37 genera. Molecular phylogeny using 6 genes uncovered six major clades within the family, along with numerous unresolved taxonomic issues. Dating of cladogenetic events and ancestral range estimation traced the origin of Nemacheilidae to Indochina around 48 million years ago. Subsequently, one branch of Nemacheilidae colonised eastern, central, and northern Asia, as well as Europe, while another branch expanded into the Burmese region, the Indian subcontinent, the Near East, and northeast Africa. These expansions were facilitated by tectonic connections, favourable climatic conditions, and orogenic processes. Conversely, aridification emerged as the primary cause of extinction events. Our study marks the first comprehensive reconstruction of the evolution of Eurasian freshwater biodiversity on a continental scale and across deep geological time.
Novel quantal analysis method reveals conservation of average excitatory synaptic charge across cortical pyramidal neurons of different sizes
Authors: Dervinis Martynas , Major Guy
Published: July 2024

In chemical synapses of the central nervous system (CNS), information is transmitted via the presynaptic release of a vesicle (or ‘quantum’) of neurotransmitter, which elicits a postsynaptic electrical response with an amplitude termed the ‘quantal size’. Measuring amplitudes of miniature postsynaptic currents (mPSCs) or potentials (mPSPs) at the cell soma is generally thought to offer a technically straightforward way to estimate quantal sizes, as each of these miniature responses (minis) is generally thought to be elicited by the spontaneous release of a single neurotransmitter vesicle. However, in large highly-branched neurons, a somatically recorded mini is typically massively attenuated compared with at its input site, and a significant fraction are indistinguishable from (or cancelled out by) background noise fluctuations. Here, using a new software package called ‘minis’, we describe a novel quantal analysis method that estimates the ‘electrical size’ of the synapse by comparing events detected in somatic recordings from the same neuron of (a)realminis and (b) background noise (minis blocked pharmacologically) withsimulatedminis added by a genetic algorithm. The estimated minis’ distributions reveal a striking inverse dependence of mean excitatory mPSP amplitude on total cell capacitance (proportional to cell size, more exactly, extracellular membrane surface area) suggesting that, in rats at least, the average charge (ca. 30 fC) injected by excitatory synapses is conserved across neocortical pyramidal neurons of different sizes.
Force monitoring reveals single trial dynamics of motor control in a stop signal task
Authors: Ramawat Surabhi , Marc Isabel B , Di Bello Fabio , Bardella Giampiero , Ferraina Stefano , Pani Pierpaolo , Brunamonti Emiliano
Published: July 2024

The Stop Signal Task (SST) has been the benchmark for studying the behavioral and physiological basis of movement generation and inhibition. In our study, we extended the scope beyond physiological findings related to muscle activity, focusing our analysis on the initial biomechanical state of the effector. By incorporating a force sensitive resistor (FSR), we continuously monitored the force applied by the effector (here the index finger) during a button release version of the SST. This modified task design allowed us to examine both the baseline force before the relevant Go signal was presented and during the covert state of movement preparation. Notably, variations in force over time in response to the Go signal revealed differences across trials where movement was either generated or successfully inhibited, depending on the amount of force during the baseline period. Specifically, higher baseline force was associated with a delayed movement generation, which simultaneously slowed down the force release, facilitating successful inhibition when requested. Our results highlight the influence of biomechanical variables in movement control, which should be accounted for by the models developed for investigating the physiology of this ability.

NEW & NOTEWORTHY

Movement involves changing the position of anatomical effectors, like a finger. The initial biomechanical state of an effector impacts movement generation and inhibition. Using the Stop-Signal task, we studied these factors by measuring the force applied to a mouse button before movement onset. Higher initial force delayed movement generation and slowed force release, aiding movement inhibition. This research links behavioral models of action-stopping with movement biomechanics, highlighting the effector’s initial state importance.
Modeling immunoglobulin light chain amyloidosis inCaenorhabditis elegans
Authors: Romeo Margherita , Barzago Maria Monica , Corbelli Alessandro , Maglioni Silvia , Ventura Natascia , Natale Carmina , Conz Andrea , Salmona Mario , Palladini Giovanni , Nuvolone Mario , Fiordaliso Fabio , Merlini Giampaolo , Diomede Luisa
Published: July 2024

Cardiomyopathy determines the prognosis of patients with immunoglobulin light chain (AL) amyloidosis, a rare systemic disease caused by the misfolding and deposition of monoclonal light chains (LCs). The reasons underlining their cardiac tropism remain unknown, and an animal model recapitulating the main pathological features of AL amyloidosis is instrumental. Taking advantage of the similarities between the vertebrate heart andC. elegans’ pharynx, we developed a new transgenic nematode expressing a human amyloidogenic λ LC whose sequence was deduced from a patient suffering from AL amyloidosis with cardiac involvement (MNH). Strains expressing a non-amyloidogenic LC (MNM) or the empty vector only (MNV) were generated as controls. At variance with controls, LCs expressed in the body-wall muscle of MNH worms formed native soluble dimeric assemblies, which were secreted and reached different organs, including the pharynx. Noteworthy, MNH worms exerted a pharyngeal impairment resembling cardiac functional impairment occurring in patients with AL, accompanied by increased radical oxygen species production and tissue ultrastructural damage. This new animal model can allow the elucidation of the mechanisms underlying the cardiac-specific tropism occurring in AL amyloidosis, providing innovative insights into the pathophysiology.
NSP4 mutation T492I drives rapid evolution of SARS-CoV-2 toward Omicron
Authors: Lin Xiaoyuan , Sha Zhou , Zhang Chunlin , Adler Julia M. , Vidal Ricardo Martin , Langner Christine , Fu Beibei , Xiong Yan , Tan Meng , Jiang Chen , Zeng Hao , Zhang Xiaokai , Li Qian , Yan Jingmin , Lu Xiaoxue , Wang Shiwei , Mao Xuhu , Kunec Dusan , Trimpert Jakob , Wu Haibo , Zou Quanming , Zhu Zhenglin
Published: July 2024

T492I, a mutation encountered in SARS-CoV-2 nonstructural protein 4 (NSP4), enhances viral replication and alters nonstructural protein cleavage, causing potential evolutionary impacts. Through comprehensive comparative analyses based on evolve-and-resequence experiments of SARS-CoV-2 wild-type and Delta strains with or without T492I, we demonstrate that NSP4 T492I not only increases the mutation rate, but also accelerates the emergence of many mutations characteristic for Omicron variants. Accordingly, viral populations that evolved from ancestors with T492I, show Omicron-biased selective forces and increases in viral replication, infectivity, immune evasion capacity, potentials for cross-species transmission and receptor-binding affinity. Aside from enhanced replication, we observed stronger epistasis regarding viral replication and infectivity in T492I than in S N501Y and NSP6 ∆SGF; this facilitates the regulation of mutation types, which can drive fast evolution of Omicron specific mutations. Our results highlight the role of an important replication-enhancing mutation in regulating the evolutionary rates and mutational trends of SARS-CoV-2.
Probing tau citrullination in Alzheimer’s disease brains and mouse models of tauopathy
Authors: Liang Huimin , Hunt Jerry B. , Ma Chao , Kovalenko Andrii , Calahatian John , Pedersen Cecelie , Lui Haiying , Li Junyan , Serrano Malina , Blazier Danielle , Watler Mallory , Rocha-Rangel Patricia , Saunders Christopher , Blair Laura J. , Breydo Leonid , Nash Kevin , Quadri Zainuddin , Kraemer Brian , Nelson Peter , Norris Christopher , Abner Erin L. , Uversky Vladimir N. , Chaput Dale , Selenica Maj-Linda B. , Lee Daniel C.
Published: July 2024

Tauopathies, which include Alzheimer’s disease (AD) share a common defining factor, namely misfolded tau protein. However, the “upstream” etiology and downstream clinical manifestations of tauopathies are quite diverse. Tau deposition elicits different pathological phenotypes and outcomes depending on the tau strain and regional susceptibility. Posttranslational modifications (PTM) can alter tau structure, function, networks, and its pathological sequalae. We uncovered a novel PTM of tau, named citrullination, caused by peptidyl arginine deiminase (PAD) enzymes. PAD induced citrullination irreversibly converts arginine residues to citrulline, producing net loss of positive charge, elimination of pi-pi interactions, and increased hydrophobicity. We observed increased PAD2 and PAD4 in Alzheimer’s disease (AD) brain and that they both can citrullinate tau. Tau can become citrullinated by PADs at all 14 arginine residues throughout the N-terminal domain (N-term), proline-rich domain (PR), microtubule binding repeat domain (MBR), and C-terminal domain (C-term) on full length tau (2N4R). Citrullination of tau impacts fibrillization and oligomerization rates in aggregation assays. Utilizing a panel of novel citrullinated tau (citR tau) antibodies, we identified citrullination of tauin vitro, several animal models of tauopathies, and Alzheimer’s disease (AD). CitR tau increased with Braak stage and was enriched in AD brains with higher phospho-tau burden. This work provides a new area of tau biology that signifies further consideration in the emerging spectrum of tauopathies and its clinical understanding.
Structural impact of synonymous mutations in six SARS-CoV-2 Variants of Concern
Authors: Ziesel Alison , Jabbari Hosna
Published: July 2024

SARS-CoV-2 continues to spread and infect people worldwide. While most effort into characterizing variants of this virus have focused on non-synonymous changes, accumulation of synonymous mutations in different viral variants has also occurred. Here we characterize six Variants of Concern in terms of their mutational content, and make predictions regarding the impact of those mutations on potential genomic RNA secondary structure and stability. We find that synonymous mutations typically have no or modest impact to RNA secondary structure. As synonymous mutations are free from the selective pressure imposed on protein-altering mutations, the impact of synonymous mutations is largely limited to RNA secondary structure considerations. The absence of major, structure-altering synonymous mutations emphasize the importance of RNA structure, including within coding regions, to viral fitness.
Representation of visual uniformity in the lateral prefrontal cortex
Authors: Ge Yijun , Taschereau-Dumouchel Vincent , Lin Qi , Moharramipour Ali , Sun Zhouyuan , Lau Hakwan
Published: July 2024

Visual illusions tend to have early visual cortical correlates. However, this general trend may not apply to our subjective impression of a detailed and uniform visual world, which may be considered illusory given the paucity of peripheral processing. Using a psychophysically calibrated visual illusion, we assessed the patterns of hemodynamic activity in the human brain that distinguished between the illusory percept of uniformity in the periphery (i.e., Gabor patches having identical orientations) from the accurate perception of incoherence. We identified voxel patterns in the lateral prefrontal cortex that predicted perceived uniformity, which could also generalize to scene uniformity in naturalistic movies. Because similar representations of visual uniformity can also be found in the intermediate and late layers of a feedforward convolutional neural network, the perception of uniformity may involve high-level coding of abstract properties of the entire scene as a whole, that is distinct from the filling-in of specific details in early visual areas.
A pumpless and tubeless microfluidic device enables extendedin vitrodevelopment ofCryptosporidium parvum
Authors: Gunasekera Samantha , Thierry Benjamin , Cheah Edward , King Brendon , Monis Paul , Carr Jillian M. , Chopra Abha , Watson Mark , O’Dea Mark , Ryan Una
Published: July 2024

The enteric parasiteCryptosporidiumremains a treatment challenge for drinking water utilities globally due to its resistance to chlorine disinfection. However, the lack of anin vitroculture system forCryptosporidiumthat is both cost-effective and reliable remains a key bottleneck inCryptosporidiumresearch. Here we report that the microfluidic culture of HCT-8 cells under fluid shear stress enables the extended development ofCryptosporidium parvum. Specifically, the growth ofC. parvumin a user-friendly pumpless microfluidic device was assessed using immunofluorescence assays, scanning electron microscopy and quantitative PCR, which revealed that development peaked at six days post-infection but continued for ten days in total. Oocysts produced within the microfluidic device were infective to fresh HCT-8 monolayers, however these oocysts were only present at low levels. We anticipate that such microfluidic approaches will facilitate a wide range ofin vitrostudies onCryptosporidiumand may have the potential to be further developed as a routine infectivity assessment tool for the water industry.
Influence of Information Access on Organ Donation: A Questionnaire-Based Cross-Sectional Study
Authors: Costaguta Guillermo A. , Romero Andrea , Costaguta Alejandro C.
Published: July 2024

Introduction

Organ transplantation is the sole effective treatment for end-stage organ diseases. However, the availability of donor organs remains insufficient. This shortage is driven by several factors, with access to accurate information being the key determinant of an individual’s willingness to donate organs.

Methods

A cross-sectional study based on anonymous surveys conducted from January to December 2019, categorizing participants into healthcare professionals and non-healthcare individuals. Data included willingness to donate organs, reasons for refusal, age, education level, and understanding of brain death. Statistical significance was set at p<0.05.

Results

A total of 408 participants were included: 203 in the healthcare sector and 205 in the non-healthcare sector. Among healthcare professionals, 90% were willing to donate organs compared to 43% in the non-healthcare group (p<0.001). Non-healthcare respondents refused due to the fear of being alive during organ removal (74%), concerns about reduced emergency care (21%), and religious beliefs (5%). Despite these concerns, 88% acknowledged that organ donation saves lives and 95% recognized the gap between organ supply and demand. No significant differences in education levels were found between donors and non-donors, but healthcare professionals had a significantly better understanding of brain death (p<0.001). All respondents indicated that they would accept a donated organ, if needed.

Conclusion

Healthcare professionals are more inclined to be organ donors than are those outside the field. Misunderstandings among non-healthcare individuals contributed to higher refusal rates. Tailored awareness campaigns and educational programs could rectify these misconceptions, potentially improving donation rates and mitigating organ shortage crises.