bluuebunny/crossref_metadata_2025 huggingface dataset:
Sphingomonas rustica sp. nov. and Sphingomonas agrestis sp. nov., novel carotenoid-producing bacterial species isolated from farm soil
Authors: Lee Hyunji , Kim Inhyup , Park Sunho , Woo Haejin , Yook Subin , Seo Taegun
Published: October 2024

Two yellow-pigmented novel strains, designated HF-S3T and HF-S4T, were isolated from farm soil in Paju, Republic of Korea. Cells of the two strains are characteristically Gram-stain-negative, facultatively anaerobic, catalase- and oxidase-positive, non-motile and rod-shaped. Strain HF-S3T grew at 10–37 °C, while HF-S4T grew at 15–35 °C. Both strains grew at pH 5.0–12.0 and in NaCl concentrations (w/v) of 0–2.0%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that HF-S3T and HF-S4T belong to the genus Sphingomonas, with HF-S3T exhibiting 97.7, 97.6 and 97.4% similarity to Sphingomonas cannabina DM2-R-LB4T, Sphingomonas leidyi DSM 4733T and Sphingomonas canadensis FWC47T, respectively. Strain HF-S4T displayed 97.9, 97.7 and 97.6% similarity to Sphingomonas psychrotolerans Cra20T, Sphingomonas gei ZFGT-11T and Sphingomonas naasensis KIS18-15T, respectively. The DNA G+C contents of HF-S3T and HF-S4T were 67.0 and 66.5 mol%, respectively. The digital DNA–DNA hybridization and average nucleotide identity values among the novel and related type strains were 20.2–28.2% and 75.9–84.3%, respectively. They all contained C14:0 2-OH and C16:0, summed feature 8 (C18:1
ω6c and/or C18:1
ω7c) as the major fatty acids and ubiquinone-10 as the predominant respiratory quinone. Strains HF-S3T and HF-S4T were found to produce carotenoid-type pigments. Based on polyphasic taxonomic analysis, the new isolates ostensibly represent two novel species of the genus Sphingomonas, with the proposed names Sphingomonas rustica sp. nov. and Sphingomonas agrestis sp. nov. for strains HF-S3T and HF-S4T, respectively. The S. rustica and S. agrestis type strains are HF-S3T (=KACC 23554T =TBRC 18352T) and HF-S4T (=KACC 23386T =TBRC 17899T), respectively.
Squash vein yellowing virus from California emerged in the Middle East via intragenic and intergeneric recombination events in the hypervariable potyvirus P1 and ipomovirus P1a genes
Authors: Macedo M. A. , Melgarejo T. A. , Vasquez-Mayorga M. , Cespedes M. , Rojas M. R. , Turini T. A. , Batuman O. , Wintermantel W. M. , Gilbertson R. L.
Published: October 2024

We present the complete sequence of the genomic RNA of an isolate of squash vein yellowing virus (Ipomovirus cucurbitavenaflavi) from California (SqVYV-CA) and show it is a recombinant virus with a highly divergent 5′ UTR and proximal P1a gene. The evolution of SqVYV-CA involved an intrageneric event between unknown potyviruses, related to isolates of papaya ringspot virus (Potyvirus papayanuli) from the Old World, and an intergeneric event between this recombinant potyvirus (minor parent) and an isolate of SqVYV from Israel (SqVYV-IL) (major parent). These events occurred in mixed infections and in the potyvirus P1 and ipomovirus P1a recombination hotspots and resulted in SqVYV-CA having a potyvirus 5′ UTR and chimeric P1-P1a gene/protein and the remainder of the genome from SqVYV-IL. The SqVYV-CA chimeric P1-P1a gene is under positive selection, and the protein is intrinsically disordered and may localize to the nucleus via nuclear localization signals in the P1 part. The C-terminal SqVYV-IL P1a part also diverged but retained the conserved serine protease motif. Furthermore, substantial divergence in SqVYV isolates from the Middle East was associated with genetic drift and a long evolutionary history in this region. The finding that the host range and symptomatology in cucurbits of SqVYV-CA is similar to those of SqVYV from Florida and SqVYV-IL, indicated that the recombinant part of the genome had no obvious effect on the virus–host interaction. A divergent part of the P1 sequence of the SqVYV-CA P1-P1a gene was used to develop a primer pair and RT-PCR test for specific detection of SqVYV-CA. This test was used to detect spread of SqVYV-CA to a new production area of California in 2021 and 2022. Together, these results demonstrate (i) a high level of genetic diversity exists among isolates of SqVYV and involved intra- and intergeneric recombination and genetic drift (mutation), (ii) evidence that SqVYV originated in the Middle East and that there were independent introductions into the New World and (iii) the remarkable genetic flexibility of the 5′ proximal genes of these viruses.
Evaluating Long-Term Autonomic Dysfunction and Functional Impacts of Long COVID: A Follow-Up Study
Authors: Eastin Ella F. , Machnik Jannika V. , Larsen Nicholas W. , Seliger Jordan , Geng Linda N. , Bonilla Hector , Yang Phillip C. , Stiles Lauren E. , Miglis Mitchell G.
Published: October 2024

Background

The longitudinal prevalence and autonomic symptom burden in Long COVID patients is not well-established.

Objective

Assess the duration and severity of autonomic dysfunction in adults with Long COVID and evaluate its impact on function and quality of life.

Design

A follow-up survey of a subset of participants from a cross-sectional online survey of adults with Long COVID. Multivariable logistic regression identified predictors of moderate to severe autonomic dysfunction.

Participants

526 adults (ages 20-65) with a history of Long COVID

Main measures

The Composite Autonomic Symptom 31 (COMPASS-31) score, the RAND 36-Item Health Survey, the prevalence of new postural orthostatic tachycardia syndrome (POTS), and predictors of autonomic dysfunction, including POTS

Key results

71.9% of Long COVID patients had a COMPASS-31 score >20, suggestive of moderate to severe autonomic dysfunction. The median symptom duration was 36 [30-40] months, reaching up to 3.5 years after SARS-CoV-2 infection. 37.5% of Long COVID patients could no longer work or had to drop out of school due to their Long COVID illness. 40.5% were newly diagnosed with POTS following SARS-CoV-2 infection.

Conclusions

Evidence of persistent moderate to severe autonomic dysfunction was seen in 71.9% of Long COVID patients in our study, with a 36-month median symptom duration, suggesting that enduring autonomic dysfunction is highly prevalent in the Long COVID population. Moderate to severe autonomic dysfunction was significantly correlated with impaired function and capacity, highlighting the need to address POTS and other manifestations of autonomic dysfunction as a key component of Long COVID management.
B cells imprinted by ancestral SARS-CoV-2 develop pan-sarbecovirus neutralization in immune recalls
Authors: Chen Xixian , Li Ling , Du Ruiping , Wang Zuowei , Li Yunjian , Sun Yi , Qin Rongrong , Feng Hualong , Hu Lin , Chen Xuanyi , Lu Maosheng , Huang Xueyan , Jiang Liwei , Zuo Teng
Published: October 2024

A key question on ancestral SARS-CoV-2 immune imprinting is to what extent imprinted B cells can develop neutralizing breadth and potency in immune recalls. Here, we longitudinally tracked B cells recognizing wild-type spike in two individuals, who were sequentially infected by Omicron variants after receiving mRNA vaccines. Functional and genetic analysis of 632 monoclonal antibodies (mAbs) from those B cells reveals that mAbs cloned after second infection have dramatically enhanced neutralizing breadth and potency, which is attributed to recall and maturation of pre-existing memory B cells. Among the 11 mAbs that potently neutralize SARS-CoV-2 variants from wild-type to KP.3, 5 mAbs are classified into public clonotypes encoded by IGHV3-53 or IGHV3-66, whereas the rest belong to a rarely reported clonotype encoded by IGHV3-74. Notably, IGHV3-74 mAbs can also broadly neutralize other sarbecoviruses by targeting a novel epitope on receptor-binding domain of spike. These results support that ancestral SARS-CoV-2 immune imprinting can be harnessed in developing pan-SARS-CoV-2 and even pan-sarbecovirus vaccines.

Chen et al. demonstrate that B cells imprinted by ancestral SARS-CoV-2 have tremendous potential to develop neutralizing breadth and potency in repeated immune recalls driven by Omicron variants, implicating that ancestral SARS-CoV-2 immune imprinting can be harnessed in developing pan-SARS-CoV-2 and even pan-sarbecovirus vaccines.
Sugar-rich foods exacerbate antibiotic-induced microbiome injury
Authors: Dai Anqi , Adintori Peter A , Funnell Tyler , Jogia William P , Fei Teng , Waters Nicholas R , Rangesa Madhumitha , Ballweg Annamaria , Gipson Brianna , Raj Sandeep , Hayase Eiko , Markey Kate A , Burgos da Silva Marina , Miltiadous Oriana , Brambilla Corrado Zuanelli , Buchan Marissa Lubin , Peets Tatnisha , Gradissimo Ana , Smith Natalie , Katsamakis Zoe , Warren Adam , Amoretti Luigi A , Duan Caichen , Zhang Chenzhen , Matheis Fanny , Sullivan Alexis P , Slingerland John B , Clurman Annelie , Brereton Daniel G , Giardina Paul A , Gomes Antonio L C , Johnson Abigail J , Knights Dan , Jenq Robert R , Perales Miguel-Angel , Giralt Sergio A , Schluter Jonas , van den Brink Marcel R M , Peled Jonathan
Published: October 2024

Intestinal microbiota composition is implicated in several diseases; understanding the factors that influence it are key to elucidating host-commensal interactions and to designing microbiome-targeted therapies. We quantified how diet influences microbiome dynamics in hospitalized patients. We recorded 9,419 meals consumed by 173 patients undergoing hematopoietic cell transplantation and profiled the microbiome in 1,009 longitudinally collected stool samples from 158 of them. Caloric intake was correlated with fecal microbiota diversity. Bayesian inference revealed associations between intake of sweets or sugars during antibiotic exposure with microbiome disruption, as assessed by low diversity or expansion of the pathobiont Enterococcus. We validated this observation experimentally, finding that sucrose exacerbated antibiotic-induced Enterococcus expansion in mice. Taken together, our results suggest that avoiding sugar-rich foods during antibiotic treatment may reduce microbiome injury.
End-to-end multimodal deep learning for real-time decoding of months-long neural activity from the same cells
Authors: He Yichun , Marin-Llobet Arnau , Sheng Hao , Liu Ren , Liu Jia
Published: October 2024

Long-term, stable, and real-time decoding of behavior-dependent neural dynamics from the same cells is critical for brain-computer interfaces (BCIs) and for understanding neural evolution during learning, and memory, and disease progression. Recent advances in flexible and high-density electrodes have enabled the stability required for long-term tracking but generate vast datasets that challenge existing analysis methods. Current spike sorting approaches rely heavily on manual curation and lack scalability for large-scale, real-time processing. Here, we introduce AutoSort, an end-to-end multimodal deep neural network-based method that enables real-time tracking and decoding of the same neurons over months. AutoSort uses a scalable strategy by learning deep representations from initial recordings and applying the trained model in real-time. It integrates multimodal features, including waveform features, distribution patterns, and inferred neuron spatial locations, to ensure robustness and accuracy. AutoSort outperforms existing methods in both simulated and long-term recordings, reducing computational demands by using only 10% of the time and 25% of the memory compared to conventional methods. By combining AutoSort with high-density flexible probes, we track neural dynamics in real-time during motor learning and skill acquisition over 2 months, capturing intrinsic neural manifold drift, stabilization, and post-learning representational drift. AutoSort offers a promising solution for studying long-term neural intrinsic dynamics and enabling real-time BCI decoding.
Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation
Authors: Fricke Michel , Mechel Anna , Twellsieck Björn , Grein Jessica M. , Cima-Omori Maria-Sol , Zweckstetter Markus , Holzbaur Erika L.F. , Boecker C. Alexander
Published: October 2024

Parkinson disease-causing mutations in theLRRK2gene hyperactivate LRRK2 kinase activity, leading to increased phosphorylation of a subset of RAB GTPases, which are master regulators of intracellular trafficking. In neurons, processive retrograde transport of autophagosomes is essential for autophagosome maturation and effective degradation of autophagosomal cargo in the axon. We found that knockout of the LRRK2-counteracting RAB phosphatase PPM1H resulted in a gene dose-dependent disruption of the axonal transport of autophagosomes, leading to impaired degradation of axonal alpha-synuclein (aSyn), a key protein in Parkinson disease pathophysiology. Defective autophagosome transport and impaired aSyn degradation also correlated with increased aSyn aggregation in primaryPPM1Hknockout neurons exposed to preformed fibrils of aSyn, an effect that was dependent on LRRK2 kinase activity. Thus, our results link LRRK2-mediated RAB hyperphosphorylation to aSyn pathology in Parkinson disease and further establish a role for impaired autophagy in Parkinson disease pathophysiology.
A comprehensive engineering strategy improves potency and manufacturability of a near pan-neutralizing antibody against HIV
Authors: Sajadi Mohammad M. , Abbasi Abdolrahim , Tehrani Zahra Rikhtegaran , Siska Christine , Clark Rutilio , Chi Woo , Seaman Michael S. , Mielke Dieter , Wagh Kshitij , Liu Qingbo , Jumpa Taylor , Ketchem Randal R. , Nguyen Dung N. , Tolbert Willaim D. , Pierce Brian G. , Atkinson Ben , Deming Derrick , Sprague Megan , Asakawa Andrew , Ferrer David , Dunn Yasmin , Calvillo Sarah , Yin Rui , Guest Johnathan D. , Korber Bette , Mayer Bryan T. , Sato Alicia H. , Ouyang Xin , Foulke Scott , Habibzadeh Parham , Karimi Maryam , Aslanabadi Arash , Hojabri Mahsa , Saadat Saman , Zareidoodeji Roza , Kędzior Mateusz , Pozharski Edwin , Heredia Alonso , Montefiori David , Ferrari Guido , Pazgier Marzena , Lewis George K. , Jardine Joseph G. , Lusso Paolo , DeVico Anthony
Published: October 2024

Anti-HIV envelope broadly neutralizing antibodies (bnAbs) are alternatives to conventional antiretrovirals with the potential to prevent and treat infection, reduce latent reservoirs, and/or mediate a functional cure. Clinical trials with “first generation” bnAbs used alone or in combination show promising antiviral effects but also highlight that additional engineering of “enhanced” antibodies will be required for optimal clinical utility, while preserving or enhancing cGMP manufacturing capability. Here we report the engineering of an anti-CD4 binding-site (CD4bs) bnAb, N49P9.3, purified from the plasma of an HIV elite-neutralizer. Through a series of rational modifications we produced a variant that demonstrates: enhanced potency; superior antiviral activity in combination with other bnAbs; low polyreactivity; and longer circulating half-life. Additional engineering for manufacturing produced a final variant, eN49P9, with properties conducive to cGMP production. Overall, these efforts demonstrate the feasibility of developing enhanced anti-CD4bs bnAbs with greatly improved antiviral properties as well as potential translational value.
Semisynthetic Simulation for Microbiome Data Analysis
Authors: Sankaran Kris , Kodikara Saritha , Li Jingyi Jessica , Cao Kim-Anh Lê
Published: October 2024

High-throughput sequencing data lie at the heart of modern microbiome research. Effective analysis of these data requires careful preprocessing, modeling, and interpretation to detect subtle signals and avoid spurious associations. In this review, we discuss how simulation can serve as a sandbox to test candidate approaches, creating a setting that mimics real data while providing ground truth. This is particularly valuable for power analysis, methods benchmarking, and reliability analysis. We explain the probability, multivariate analysis, and regression concepts behind modern simulators and how different implementations make trade-offs between generality, faithfulness, and controllability. Recognizing that all simulators only approximate reality, we review methods to evaluate how accurately they reflect key properties. We also present case studies demonstrating the value of simulation in differential abundance testing, dimensionality reduction, network analysis, and data integration. Code for these examples is available in an online tutorial (https://go.wisc.edu/8994yz) that can be easily adapted to new problem settings.
eQTL in diseased colon tissue identifies novel target genes associated with IBD
Authors: Nishiyama Nina C. , Silverstein Sophie , Darlington Kimberly , Kennedy Ng Meaghan M. , Clough Katelyn M. , Bauer Mikaela , Beasley Caroline , Bharadwaj Akshatha , Ganesan Rajee , Kapadia Muneera R. , Lau Gwen , Lian Grace , Rahbar Reza , Sadiq Timothy S. , Schaner Matthew R. , Stem Jonathan , Friton Jessica , Faubion William A. , Sheikh Shehzad Z. , Furey Terrence S.
Published: October 2024

Genome-wide association studies (GWAS) have identified over 300 loci associated with the inflammatory bowel diseases (IBD), but putative causal genes for most are unknown. We conducted the largest disease-focused expression quantitative trait loci (eQTL) analysis using colon tissue from 252 IBD patients to determine genetic effects on gene expression and potential contribution to IBD. Combined with two non-IBD colon eQTL studies, we identified 194 potential target genes for 108 GWAS loci. eQTL in IBD tissue were enriched for IBD GWAS loci colocalizations, provided novel evidence for IBD-associated genes such asABOandTNFRSF14, and identified additional target genes compared to non-IBD tissue eQTL. IBD-associated eQTL unique to diseased tissue had distinct regulatory and functional characteristics with increased effect sizes. Together, these highlight the importance of eQTL studies in diseased tissue for understanding functional consequences of genetic variants, and elucidating molecular mechanisms and regulation of key genes involved in IBD.
Metabolic interplay drives population cycles in a cross-feeding microbial community
Authors: Ross Tyler D. , Klausmeier Christopher A. , Venturelli Ophelia S.
Published: October 2024

Population cycles are prevalent in ecosystems and play key roles in determining their functions1,2. While multiple mechanisms have been theoretically shown to generate population cycles3–6, there are limited examples of mutualisms driving self-sustained oscillations. Using an engineered microbial community that cross-feeds essential amino acids, we experimentally demonstrate cycles in strain abundance that are robust across environmental conditions. A nonlinear dynamical model that incorporates the experimentally observed cross-inhibition of amino acid production recapitulates the population cycles. The model shows that the cycles represent internally generated relaxation oscillations, which emerge when fast resource dynamics with positive feedback drive slow changes in strain abundance. Our findings highlight the critical role of resource dynamics and feedback in shaping population cycles in microbial communities and have implications for biotechnology.
Increase of tropical seabirds (Sula) in the California Current Ecosystem with warmer ocean conditions
Authors: Russell Tamara M. , Pereksta David M. , Tietz James R. , Vernet Maria , Jahncke Jaime , Ballance Lisa T.
Published: October 2024

Climate change is impacting marine ecosystems in the California Current Ecosystem (CCE) through physical changes (e.g., an increase in the frequency and intensity of marine heatwaves) that manifest biologically at all trophic levels. We investigated range expansion into the CCE and correlations with environment for a group of tropical/sub-tropical seabirds. We assessed changes in the abundance (2002-2022) of five species from the genus,Sula(Cocos, Blue-footed, Red-footed, Masked, and Nazca Boobies), using a novel compilation of four data sources (at-sea surveys, n=82 observations, records from Southeast Farallon Island, n=600, the California Rare Birds Committee, n=593, andeBird-a citizen science mobile application, n= 20,529), and looked for relationships with the environment, including broad temporal and spatial scale dynamics (El Niño Southern Oscillation), local conditions where the bird was reported, and potential source conditions from Baja California Sur and the Gulf of California. All five species increased in abundance, and all, with the exception of Blue-footed, exhibited a northward range expansion by as much as 6.8 degrees latitude and increased range area of between 235-1013% within the CCE. There was increased abundance during warmer conditions (El Niño and warm SST) for Cocos, Red-footed, Masked, and Nazca Boobies, and all species increased by 692-3015% after the extreme marine heatwaves that began in late 2013. Our results document a tropical shift in seabirds of the CCE, which may present future challenges to resident species. As marine heatwaves are projected to increase in frequency and intensity, in addition to long-term warming, we hypothesize that these species will continue to expand their range northward in the CCE.
Negativeome in Early-Life Virome Studies: Characterization and Decontamination
Authors: Kuzub Nataliia , Kurilshikov Alexander , Zhernakova Alexandra , Garmaeva Sanzhima
Published: October 2024

Environmental contamination complicates the study of low-biomass microbial communities like the human gut virome. In 1,321 early-life gut viromes and 55 negative controls (NCs) from four datasets, we identified viral contaminants and their prevalence across studies. Samples and NCs were indistinguishable in genomic and ecological features, with 71.5% of samples sharing at least one identical strain with NCs. This work demonstrates the efficacy of strain-aware decontamination for preserving biological signals.
A human high-fidelity DNA polymerase holoenzyme has a wide range of lesion bypass activities
Authors: Dannenberg Rachel L. , Cardina Joseph A. , Washington Helen , Gao Shijun , Greenberg Marc M. , Hedglin Mark
Published: October 2024

During replication, lagging strand lesions are initially encountered by high-fidelity DNA polymerase (pol) holoenzymes comprised of pol δ and the PCNA sliding clamp. To proceed unhindered, pol δ holoenzymes must bypass lesions without stalling. This entails dNMP incorporation opposite the lesion (insertion) and the 5’ template nucleotide (extension). Historically, it was viewed that high-fidelity pol holoenzymes stall upon encountering lesions, activating DNA damage tolerance pathways that are ultimately responsible for lesion bypass. Our recent study of 4 prominent lesions revealed that human pol δ holoenzymes support insertion and/or bypass for multiple lesions and the extents of these activities depends on the lesion and pol δ proofreading. In the present study, we expand these analyses to other prominent lesions. Collectively, analyses of 10 lesions from both studies reveal that the insertion and bypass efficiencies of pol δ holoenzymes each span a complete range (0 – 100%). Consequently, the fates of pol δ holoenzymes upon encountering lesions are quite diverse. Furthermore, pol δ proofreading promoted holoenzyme progression at 7 of the 10 lesions and did not deter progression at any. Altogether, the results significantly alter our understanding of the replicative capacity of high-fidelity pol holoenzymes and their functional role(s) in lesion bypass.
Direct segmentation of cortical cytoarchitectonic domains using ultra-high-resolution whole-brain diffusion MRI
Authors: Pas Kristofor E. , Saleem Kadharbatcha S. , Basser Peter J. , Avram Alexandru V.
Published: October 2024

We assess the potential of detecting cortical laminar patterns and areal borders by directly clustering voxel values of microstructural parameters derived from high-resolution mean apparent propagator (MAP) magnetic resonance imaging (MRI), as an alternative to conventional template-warping-based cortical parcellation methods. We acquired MAP-MRI data with 200µm resolution in a fixed macaque monkey brain. To improve the sensitivity to cortical layers, we processed the data with a local anisotropic Gaussian filter determined voxel-wise by the plane tangent to the cortical surface. We directly clustered all cortical voxels using only the MAP-derived microstructural imaging biomarkers, with no information regarding their relative spatial location or dominant diffusion orientations. MAP-based 3D cytoarchitectonic segmentation revealed laminar patterns similar to those observed in the corresponding histological images. Moreover, transition regions between these laminar patterns agreed more accurately with histology than the borders between cortical areas estimated using conventional atlas/template-warping cortical parcellation. By cross-tabulating all cortical labels in the atlas– and MAP-based segmentations, we automatically matched the corresponding MAP-derived clusters (i.e., cytoarchitectonic domains) across the left and right hemispheres. Our results demonstrate that high-resolution MAP-MRI biomarkers can effectively delineate three-dimensional cortical cytoarchitectonic domains in single individuals. Their intrinsic tissue microstructural contrasts enable the construction of whole-brain mesoscopic cortical atlases.
Soil microarthropod community assembly at the micro spatial scale - A microcosm manipulation study
Authors: Dirilgen T. , Bolger T.
Published: October 2024

Our understanding of soil microarthropod (Acari and Collembola) community assembly and dynamics is somewhat limited compared to aboveground communities. Understanding the processes involved in assembly and the spatial scales at which they occur would help answer the age old question of how so many species and individuals can coexist in soil. We use a microcosm experiment using intact soil cores to explore the processes of selection and dispersal taking place at the micro-spatial scale. We do this by manipulating available pore space and population density, which allows us to indirectly investigate the role of dispersal and biotic interactions in shaping microarthropod community dynamics. Results suggest that there are processes limiting abundance and that communities are sometimes held at abundances below those which the environment could accommodate by abiotic factors. Food and space did not appear to drive the observed patterns; however, findings suggest that abiotic factors may influence dynamics in the field.
Cross-Linguistic Analysis of Speech Markers: Insights from English, Chinese, and Italian Speakers
Authors: Santi Gaia C. , Catricalà Eleonora , Kwan Stephanie , Wong Anson , Ezzes Zoe , Wauters Lisa , Esposito Valentina , Conca Francesca , Gibbons Daniela , Fernandez Eric , Santos-Santos Migual A. , TaFu Chen , Li-Ying Kwan-Chen , Lo R , Tsoh J , Chan Lung-Tat , Garcia Adolfo M. , de Leon Jessica , Miller Zachary , Vonk Jet M.J. , Bruffaerts Rose , Grasso Stephanie M. , Allen Isabel E. , Cappa Stefano F. , Gorno-Tempini Maria Luisa , Tee Boon Lead
Published: October 2024

Cross-linguistic studies with healthy individuals are vital, as they can reveal typologically common and different patterns while providing tailored benchmarks for patient studies. Nevertheless, cross-linguistic differences in narrative speech production, particularly among speakers of languages belonging to distinct language families, have been inadequately investigated. Using a picture description task, we analyze cross-linguistic variations in connected speech production across three linguistically diverse groups of cognitively normal participants—English, Chinese (Mandarin and Cantonese), and Italian speakers. We extracted 28 linguistic features, encompassing phonological, lexico-semantic, morpho-syntactic, and discourse/pragmatic domains. We utilized a semi-automated approach with Computerized Language ANalysis (CLAN) to compare the frequency of production of various linguistic features across the three language groups. Our findings revealed distinct proportional differences in linguistic feature usage among English, Chinese, and Italian speakers. Specifically, we found a reduced production of prepositions, conjunctions, and pronouns, and increased adverb use in the Chinese-speakers compared to the other two languages. Furthermore, English participants produced a higher proportion of prepositions, while Italian speakers produced significantly more conjunctions and empty pauses than the other groups. These findings demonstrate that the frequency of specific linguistic phenomena varies across languages, even when using the same harmonized task. This underscores the critical need to develop linguistically tailored language assessment tools and to identify speech markers that are appropriate for aphasia patients across different languages.
Verifying Infectious Disease Scenario Planning for Geographically Diverse Populations
Authors: Conrad Jessica R. , Fenimore Paul W. , Moran Kelly R. , Eisenberg Marisa C.
Published: October 2024

In the face of the COVID-19 pandemic, the literature saw a spike in publications for epidemic models, and a renewed interest in capturing contact networks and geographic movement of populations. There remains a general lack of consensus in the modeling community around best practices for spatiotemporal epi-modeling, specifically as it pertains to the infection rate formulation and the underlying contact or mixing model.

In this work, we mathematically verify several common modeling assumptions in the literature, to prove when certain choices can provide consistent results across different geographic resolutions, population densities and patterns, and mixing assumptions. The most common infection rate formulation, a computationally low costper capitainfection rate assumption, fails the consistency tests for heterogeneous populations and non-symmetric mixing assumptions. The largest numerical errors occur in the limit of lowest symmetry, whether as sparse geography or preferential travel to highly-populated locations. Future modeling efforts in spatiotemporal disease modeling should be wary of this limitation, particularly when working with more heterogenous or less dense populations.

Our results provide guidance for testing that a model preserves desirable properties even when model inputs mask potential problems due to symmetry or homogeneity. We also provide a recipe for performing this type of validation with the objective of strengthening decision support tools.

Highlights

Define common modeling options from the literature for spatiotemporal epidemic models

Verify common modeling assumptions are consistent for varying population densities and patterns, resolutions, and underlying mixing or contact assumptions

Provide simulation examples of model misspecification and the resulting implications on scenario planning
Enhancing Radiographic Diagnosis: CycleGAN-based methods for reducing cast shadow artifacts in wrist radiographs
Authors: Norris Stanley A , Carrion Daniel , Ditchfield Michael , Gubser Manuel , Seah Jarrel , Badawy Mohamed K
Published: October 2024

Objective

We extend existing techniques by using generative adversarial network (GAN) models to reduce the appearance of cast shadows in radiographs across various age groups.

Materials and Methods

We retrospectively collected 12000 adult and pediatric wrist radiographs, evenly divided between those with and without casts. The test subset consisted of 100 radiographs with cast and 100 without cast. We extended the results from a previous study that employed CycleGAN by enhancing the model using a perceptual loss function and a self-attention layer.

Results

The CycleGAN model which incorporates a self-attention layer and perceptual loss function delivered the best quantitative performance. This model was applied to images from 20 cases where the original reports recommended CT scanning or repeat radiographs without the cast, which were then evaluated by radiologists for qualitative assessment. The results demonstrated that the generated images could improve radiologists’ diagnostic confidence, in some cases leading to more decisive reports. Where available, the reports from follow-up imaging were compared with those produced by radiologists reading AI-generated images. Every report, except two, provided identical diagnoses as those associated with follow-up imaging. The ability of radiologists to perform robust reporting with downsampled AI-enhanced images is clinically meaningful and warrants further investigation. Additionally, radiologists were unable to distinguish AI-enhanced from unenhanced images.

Conclusion

These findings suggest the cast suppression technique could be integrated as a tool to augment clinical workflows, with the potential benefits of reducing patient doses, improving operational efficiencies, reducing delays in diagnoses, and reducing the number of patient visits.
Roles of community and sexual contacts as drivers of clade I mpox outbreaks
Authors: Murayama Hiroaki , Asakura Toshiaki R. , Dickens Borame L. , Foo Jen Han , Jin Shihui , Mukadi Patrick K. , Ejima Keisuke , Jung Sung-mok , Nishi Akihiro , Prem Kiesha , Endo Akira
Published: October 2024

Initial investigation into the emerging mpox outbreak of novel clade Ib in eastern Democratic Republic of the Congo has identified signs of sustained human-to-human transmission and epidemiological links to sexual contacts involving female sex workers (FSWs), which have not been observed in previous clade Ia outbreaks. Using mathematical models incorporating age-dependent contact patterns, we quantified the role of frequent sexual interactions as opposed to community contacts in the clade Ib dynamics and found that this additional mode of transmission could explain its increased outbreak potential compared with clade Ia. As with the globally-circulating clade IIb transmitted predominantly among men who have sex with men, our findings reinforce the importance of protecting key population groups, specifically FSWs for clade Ib, in controlling ongoing mpox outbreaks.
The case of alternatives to opioids: How much do physician characteristics matter when treating a diverse population?
Authors: Alva Maria L. , Liu Siying
Published: October 2024

Rationale

There is little understanding of the prescription patterns of alternatives to opioids (ALTOS). Monitoring gender and racial health disparities can help with healthcare planning, workforce training, patient education, and awareness.

Objective

This study asks whether healthcare professionals, when treating patients of the same race and sex, increase their likelihood of prescribing ALTOs relative to opioids.

Methods

We use national Medicare Part D data from 2013 to 2017 and a machine-learning algorithm informed by census data to define the race of prescribers. We use multivariate regression models to understand the impact of race and sex biases on the extensive margin (e.g., percentage of people receiving ALTOs) and the intensive margin (e.g., the number of ALTOs prescriptions per capita).

Results

Between 2013 and 2017, there has been an 8.7% increase in the prescriptions of ALTOs. The number of beneficiaries receiving ALTOs increased by 11.4%. In 2017, the number of ALTOs prescriptions per capita written as a fraction of all painkillers was 45%, and the number of beneficiaries receiving ALTOs prescriptions as a fraction of people receiving at least one form of painkillers (ALTOs or opioids) was 49%. A male doctor is 20.4% more likely to prescribe ALTOs as the percentage of same-sex patients increases. A white doctor is 7.4% more likely to prescribe ALTOs as the percentage of same-race patients increases, even when controlling for the socioeconomic status of patients, their age and risk factor, and the state and specialty of the prescriber.

Conclusion

Sex and race concordance between providers and patients are significantly associated with prescribing alternatives to opioids. These systematic differences could be addressed by supporting diversity in the workforce, training, and increasing the minimum amount of time a visit should last.
DeepEXPOKE: A Deep Learning Framework with Polygenic Risk Scores as Knockoffs for Deconvoluting Genetic and Non-Genetic Exposure Risks in Sepsis and Coronary Heart Disease
Authors: Sriram Aditya , Bohn Rebecca , Kernan Kate , Carcillo Joseph , Kim Soyeon , Park Hyun Jung
Published: October 2024

The exposome refers to the totality of environmental, behavioral, and lifestyle exposures an individual experiences throughout one’s lifetime. Due to the modifiability of exposures, identifying the risk exposures on a disease is crucial for effective intervention and prevention of the disease. However, traditional analytical methods struggle to capture the complexities of exposome data: nonlinear effects, correlated exposures, and potential interplay with genetic effects. To address these challenges and accurately estimate exposure effects on complex diseases, we developed DeepEXPOKE, a deep learning framework integrating two types of knockoff features: statistical knockoffs (statKO) and polygenic risk score as knockoffs (PRSKO). DeepEXPOKE-statKO controls exposure correlation and DeepEXPOKE-PRSKO isolates genetic effects, while both can capture nonlinear effects. We applied DeepEXPOKE to predict outcomes of two significant diseases with distinct etiology and clinical presentation: sepsis and coronary heart disease (CHD), demonstrating its performance in comparison to existing machine learning methods. Furthermore, both DeepEXPOKE-PRSKO and DeepEXPOKE-statKO identified metabolites such as glucose and triglycerides as risk factors for sepsis and suggested that their effects are primarily at the non-genetic level, consistent with the role of metabolites in responding to environmental factors. Additionally, DeepEXPOKE-PRSKO uniquely identified asthma as a sepsis risk factor and suggested its effect is partially at the genetic level, offering insights into the conflicting associations observed between the genome data studies and patient data analysis regarding asthma and sepsis risk. Overall, DeepEXPOKE offers a novel DNN approach for identifying and interpreting exposure risk factors, advancing our understanding of complex diseases.
‘Identification of RING E3 pseudoligases in the TRIM protein family’
Authors: Dudley-Fraser Jane , Esposito Diego , McPhie Katherine , Morley-Williams Coltrane , Auchynnikava Tania , Rittinger Katrin
Published: October 2024

TRIpartite Motif (TRIM) family proteins have diverse roles across a broad variety of cellular functions, which are largely presumed to depend on their ubiquitin E3 ligase activity, conferred by a RING domain. However, recent reports have shown that some TRIMs lack detectable ubiquitination activity in isolation, despite containing a RING domain. Here, we present parallelin cellulo,in vitro, andin silicostructure-function analyses of the ubiquitin E3 ligase activity and RING domain structural characteristics of whole TRIM protein family. In-depth follow-up studies of this comprehensive dataset reveals a number of ‘pseudoligases’, whose RING domains have structurally diverged at either the homodimerisation or E2∼ubiquitin interfaces, thereby disrupting their ability to catalyse ubiquitin transfer. Together, these data raise intriguing open questions regarding the unknown TRIM functions in physiology and disease.

Graphical Abstract
Lineage-aware evolutionary analysis of hepatitis C virus within-host dynamics
Authors: Zhao Lele , Hall Matthew , Giridhar Prahalad , Ghafari Mahan , Kemp Steven , Chai Haiting , Klenerman Paul , Barnes Eleanor , Ansari M. Azim , Lythgoe Katrina
Published: October 2024

Analysis of viral genetic data has previously revealed distinct within-host population structures in both untreated and interferon-treated chronic hepatitis C virus (HCV) infections. While multiple subpopulations persisted during the infection, each subpopulation was observed only intermittently. However, it was unknown whether similar patterns were also present after Direct Acting Antiviral (DAA) treatment, where viral populations were often assumed to go through narrow bottlenecks. Here we tested for the maintenance of population structure after DAA treatment failure. We analysed whole-genome next-generation sequencing data generated from a randomised study using DAAs (the BOSON study). We focused on samples collected from patients (N=84) who did not achieve sustained virological response (i.e. treatment failure) and had sequenced virus from multiple timepoints. For each individual, we tracked concordance in nucleotide variant frequencies through time. Using a sliding window approach, we applied sequenced-based and tree-based clustering algorithms across the entire HCV genome. Finally, we reconstructed viral haplotypes and estimated lineage specific within-host divergence rates from the haplotype phylogenies. Distinct viral subpopulations were maintained among a high proportion of individuals post DAA treatment failure. Using maximum likelihood modelling and model comparison, we found an overdispersion of viral evolutionary rates among individuals, and significant differences in evolutionary rates between lineages within individuals. These results suggest the virus is compartmentalised within individuals, with the varying evolutionary rates due to different viral replication rates or different selection pressures. We propose lineage awareness in future analyses of HCV evolution and infections to avoid conflating patterns from distinct lineages, and to recognise the likely existence of unsampled subpopulations.
Integration of the DD-genome reshapes gene transcription, chromatin architecture and metabolome of allohexaploid wheat leading to enhanced adaptability
Authors: Liu Yanyan , Zhu Tao , Zhou Xinkai , Chen Wei , He Chao , Wang Xin , Chen Chuanye , Wei Jiaqi , Lan Caixia , Liu Mengmeng , Su Handong , Li Qiang , Hu Xin , Bi Siteng , Ouyang Weizhi , Li Xingwang , Mao Hailiang , Kishi Masahiro , Kaufmann Kerstin , Fernie Alisdair R. , Chen Dijun , Yan Wenhao
Published: October 2024

The integration, through hybridization, of the DD genome into domesticated tetraploid wheat gave rise to allohexaploid wheat, the most cultivated wheat globally growing across diverse environmental conditions. However, the regulatory basis of this integration on increased environmental adaptability in allohexaploid remains largely unexplored. Here, we investigated the change of transcriptome, epigenome as well as the chromatin interactome, and metabolome in three independent polyploidization events representing DD genome integration. Our findings reveal that polyploidization events induce the activation of defense-related genes through comprehensive reorganization of epigenome and chromatin architecture. DD integration not only brings an additional gene copy but also activates the homoeologs existing in the A and B subgenomes through chromatin interactions. Furthermore, secondary metabolites represented by alkaloids and flavonoids that are crucial for environmental adaptation, are significantly enriched following polyploidization. Thus, hexaploid wheat exhibits enhanced tolerance to alkalinity, UV-B light stress and high salt conditions was observed. These results highlight the indispensable role of DD genome integration in the adaptability of allohexaploid wheat during its evolution.
β-adrenergic blockers increase cAMP and stimulate insulin secretion through a PKA/RYR2/TRPM5 pathway in pancreatic β-cells in vitro
Authors: Murao Naoya , Morikawa Risa , Seino Yusuke , Shimomura Kenju , Maejima Yuko , Yamada Yuichiro , Suzuki Atsushi
Published: October 2024

β-adrenergic blockers (β-blockers) are extensively used to inhibit β-adrenoceptor activation and subsequent cAMP production in many cell types. In this study, we characterized the effects of β-blockers on mouse pancreatic β-cells. Unexpectedly, high doses (100 μM) of β- blockers (propranolol and bisoprolol) led to a 5–10 fold increase in cAMP levels, enhanced intracellular influx, and stimulated a 2–4 fold increase in glucose-and glimepiride-induced insulin secretion in MIN6-K8 clonal β-cells and isolated mouse pancreatic islets. These effects were observed despite minimal expression of β-adrenoceptors in these cells. Mechanistically, cAMP increase led to ryanodine receptor 2 (RYR2) phosphorylation via protein kinase A (PKA), triggering Ca2+-induced Ca2+release (CICR). CICR then activates transient receptor potential cation channel subfamily M member 5 (TRPM5), resulting in increased Ca2+influx via voltage-dependent Ca2+channels. These effects contradict the conventional understanding of the pharmacology of β-blockers, highlighting the variability in β-blocker actions depending on the experimental context.

Graphical abstract

At high concentrations (> 10 μM), the β-adrenergic blocker propranolol paradoxically increased intracellular cAMP levels in pancreatic β-cells. This leads to PKA-induced RYR2 phosphorylation and extracellular Ca2+influx, leading to CICR from the ER. CICR activated TRPM5, which augmented β-cell electrical activity, extracellular Ca2+influx, and insulin secretion.
Mechanistic insights into the activity of SARS-CoV-2 RNA polymerase inhibitors using single-molecule FRET
Authors: Groves Danielle , Cunnison Rory , McMahon Andrew , Fan Haitian , Sharps Jane , Deng Adrian , Keown Jeremy R , Fodor Ervin , Robb Nicole C
Published: October 2024

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has resulted in significant global mortality and disruption. Despite extensive research, the precise molecular mechanisms underlying SARS-CoV-2 replication remain unclear. To address this, we developed a single-molecule Forster resonance energy transfer (smFRET) assay to directly visualize and analyse in vitro RNA synthesis by the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). We purified the minimal replication complex, comprising nsp12, nsp7, and nsp8, and combined it with fluorescently labelled RNA substrates, enabling real-time monitoring of RNA primer elongation at the single-molecule level. This platform allowed us to investigate the mechanisms of action of key inhibitors of SARS-CoV-2 replication. In particular, our data provides evidence for remdesivir's mechanism of action, which involves polymerase stalling and subsequent chain termination dependent on the concentration of competing nucleotide triphosphates. Our study demonstrates the power of smFRET to provide dynamic insights into SARS-CoV-2 replication, offering a valuable tool for antiviral screening and mechanistic studies of viral RdRp activity.