bluuebunny/crossref_metadata_2025 huggingface dataset:
Construct Validity Testing of the Provider Co-Management Index to Measure Shared Care in Provider Dyads
Authors: Norful Allison A. , Dierkes Andrew , de Jacq Krystyna , Brewer Katherine C.
Published: February 2024

Background

Co-management encompasses the dyadic process between two health care providers. The Provider Co-Management Index (PCMI) was initially developed as a 20-item instrument across three theory-informed subscales.

Objective

This study aimed to establish construct validity of the PCMI with a sample of primary care providers through exploratory and confirmatory factor analyses.

Methods

We conducted a cross-sectional survey of primary care physicians, nurse practitioners, and physician assistants randomly selected from the IQVIA database across New York State. Mail surveys were used to acquire a minimum of 300 responses for split sample factor analyses. The first subsample (derivation sample) was used to explore factorial structure by conducting an exploratory factor analysis. A second (validation) sample was used to confirm the emerged factorial structure using confirmatory factor analysis. We performed iterative analysis and calculated good fit indices to determine the best-fit model.

Results

There were 333 responses included in the analysis. Cronbach's alpha was high for a 3-item per dimension scale within a one-factor model. The instrument was named PCMI–9 to indicate the shorter version length.

Discussion

This study established the construct validity of an instrument that scales the co-management of patients by two providers. The final instrument includes 9 items on a single factor using a 4-point, Likert-type scale. Additional research is needed to establish discriminant validity.
Histologic Manifestations of Gastrointestinal Adenovirus Infection After Stem Cell Transplant
Authors: Hissong Erika , Arora Kshitij , Andy Caroline , Jessurun Jose , Yantiss Rhonda K.
Published: February 2024

Adenovirus can cause severe disease in hematopoietic stem cell transplant (HSCT) patients. Histopathologic features of this infection in gastrointestinal biopsies and their distinction from graft-versus-host disease (GVHD) have been incompletely studied. We retrospectively identified patients with gastrointestinal adenovirus infection. H&E-stained sections were reviewed and the histologic features were recorded. The extent of immunostaining was determined using a semiquantitative scale and a maximum number of positive cells per high-power field. Information regarding the clinical course and endoscopic findings were obtained from the electronic medical records. The study group included 32 HSCT patients. Most (81%) presented with diarrhea and detectable virus in the serum. Twenty patients had multiorgan involvement in the gastrointestinal tract, mostly in the duodenum (62%) and colon (56%). Characteristic features included apoptotic epithelial cells with nuclear disarray (84%) and tufted aggregates of degenerating epithelial cells (69%), the latter of which was more commonly seen in the study population more than a control group of HSCT patients with GI involvement by GVHD. Viral inclusions were limited to the superficial epithelium in 59% of samples, and the density of viral inclusions within biopsies was variable (grade 1: 40%, grade 2: 38%, and grade 3: 22%). Following therapy, 10 patients (30%) improved and 14 (42%) had progressive disease. Patients with disease progression were often older (64 vs. 36 years, P=0.01) with higher serologic viral loads, prior history of GVHD, multifocal involvement, and increased number and density of immunoreactive nuclei. Adenovirus infection elicits a spectrum of histologic changes that can simulate or occur in combination with gastrointestinal GVHD. Patients with progressive disease are more likely to have high viral loads and more extensive infection of the gastrointestinal tract.
Antimicrobial resistance and molecular characteristics of Neisseria gonorrhoea isolates in Ghana
Authors: Musah Haris Sualah , Addy Francis , Dufailu Osman Adamu
Published: February 2024

Introduction. Gonorrhoea is a disease associated with humans and caused by Neisseria gonorrhoea. N. gonorrhoea’s ability to evolve and evade various treatment regimens can lead to untreatable gonorrhoea. In the absence of a viable vaccine and a national database on the antimicrobial resistance (AMR) and molecular characteristics of N. gonorrhoea, and with reliance on a syndromic management regime, continuous national antimicrobial resistance surveillance and molecular characterization of N. gonorrhoea remain imperative. Only two gonococcal studies have described N. gonorrhoea’s molecular characteristics linked to AMR in Ghana.

Methods. Secondary N. gonorrhoea isolates (n=4) were collected from two metropolises in Ghana: Tamale in the northern sector (n=1) and Accra in the southern sector (n=3). The isolates were confirmed and characterized using polymerase chain reaction (PCR) targeting the porB and tbpB genes, and the disc diffusion method was used to evaluate AMR. N. gonorrhoea multi-antigen sequence typing (NG-MAST) and porin B (porB) gene sequence analyses were employed to reveal the molecular epidemiology and evolutionary trajectory, respectively.

Results. All four isolates showed resistance to at least four of the tested antibiotics. One isolate showed resistance to all seven antibiotics, i.e. ceftriaxone, azithromycin, ciprofloxacin, tetracycline, erythromycin, togamycin and penicillin. NG-MAST typing revealed isolate S3 (MZ313864) as ST211. The locus of S2 (MZ313863) (transferrin-binding protein B; tbpB) was identified as tbpB1844, and its porB locus, as porB6412, with only 4 closely related variants but with 15 nucleotide differences. However, its sequence type does not exist. The porB analysis identified isolate S3 (MZ313864) to be found globally, while S2 (MZ313863) is unique to this study.

Discussion. Despite the small number of isolates tested, this study recorded multidrug resistance and previously unknown gonococcal variants based on porB gene. Additionally, the molecular typing schemes revealed a disparity between NG-MAST and the National Center for Biotechnology Information (NCBI) platforms. There is a need for continuous gonococcal AMR and molecular surveillance in Ghana to contribute to the global efforts to describe circulating strains and support proper application of the syndromic management regime to gonorrhoea.
Glycomyces niveus sp. nov., a novel actinomycete isolated from sandy soil
Authors: Yang Xilang , Cao Hanshui , Xu Xi , Xie Jiayue , Chen Jie , Xiang Wensheng , Zhao Junwei , Wang Xiangjing
Published: February 2024

A novel mycelium-forming actinomycete, designated strain NEAU-S30T, was isolated from the sandy soil of a sea beach in Shouguang city, Shandong province, PR China. The strain developed long chains of non-motile cylindrical spores with smooth surfaces on aerial mycelia. The results of a polyphasic taxonomic study indicated that NEAU-S30T represented a member of the genus
Glycomyces
. The results of 16S rRNA gene sequence analysis indicated that NEAU-S30T was closely related to ‘Glycomyces
luteolus’ (98.97 % sequence similarity), Glycomyces
algeriensis (98.90 %), ‘Glycomyces tritici’ (98.83 %) and Glycomyces lechevalierae (98.76 %). The average nucleotide identity (ANI) values between NEAU-S30T and ‘G. luteolus’ NEAU-A15, G. algeriensis DSM 44727T, ‘G. tritici’ NEAU-C2 and G. lechevalierae DSM 44724T were 87.77, 87.53, 87.41 and 87.80 %, respectively. The digital DNA G+C content of the genomic DNA was 70.5 %. The whole-cell sugars contained ribose and xylose. The predominant menaquinones were MK-10(H2), MK-10(H4) and MK-10(H6). The predominant fatty acids were anteiso-C15 : 0, iso-C16 : 0, anteiso-C17 : 0 and iso-C15 : 0. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphoglycolipid, phosphatidylinositol, phosphatidylinositol mannoside and an unidentified glycolipid. On the basis of the results of comparative analysis of genotypic, phenotypic and chemotaxonomic data, the novel actinomycete strain NEAU-S30T (=JCM 33975T=CGMCC 4.7890T) represents the type strain of a novel species within the genus Glycomyces, for which the name Glycomyces niveus sp. nov. is proposed.
The 4T1 breast carcinoma model possesses hybrid epithelial/mesenchymal traits linked to a highly metastatic phenotype
Authors: Herndon Mary E. , Gibson-Corley Katherine , Wallrath Lori L. , Henry Michael D. , Stipp Christopher S.
Published: February 2024

Epithelial-mesenchymal transitions (EMTs) have emerged as a mechanism for carcinomas to gain metastatic capabilities. As classically defined, EMTs entail downregulation of E-cadherin, viewed as a master enforcer of an epithelial phenotype, and upregulation of mesenchymal markers such as N-cadherin and vimentin. Contrary to this, E-cadherin appears to be retained in many invasive carcinomas and promote collective cell invasion. Therefore, major questions remain concerning the role of E-cadherin in metastasis. To investigate how E-cadherin regulates metastasis, we selected murine 4T1 breast carcinoma cells, a widely utilized model of stage IV metastatic breast cancer that retains E-cadherin expression. Using RNA interference and constitutive expression, we demonstrate that the expression level of E-cadherin does not determine 4T1 metastatic capacity in mice. Despite high levels of expression, E-cadherin is unable to confer an epithelial phenotype with stable organized cell-cell junctions. Moreover, orthotopic 4T1 tumors in mice display co-expression of E-cadherin and vimentin and contain subregions of EMT-like loss of E-cadherin. In addition, we find that 4T1 cells co-express epithelial and mesenchymal isoforms of p120-catenin. These findings support 4T1 cells as a model for carcinomas that possess hybrid traits of epithelial and mesenchymal states that promote invasion and metastasis. As such, the 4T1 model provides a platform for investigating strategies to reinstate E-cadherin’s ability to promote stable cell-cell junctions in E-cadherin-positive cancers, and for identifying which aspects of an epithelial phenotype may serve to facilitate the macroscopic growth of metastatic colonies.
Genetic Studies Highlight the Role of TET2 and INO80 in DNA Damage Response and Kidney Disease Pathogenesis
Authors: Liang Xiujie , Liu Hongbo , Hu Hailong , Zhou Jianfu , Abedini Amin , Navarro Andrea Sanchez , Klötzer Konstantin A. , Susztak Katalin
Published: February 2024

Genome-wide association studies (GWAS) have identified over 800 loci associated with kidney function, yet the specific genes, variants, and pathways involved remain elusive. By integrating kidney function GWAS, human kidney expression and methylation quantitative trait analyses, we identified Ten-Eleven Translocation (TET) DNA demethylase 2: TET2 as a novel kidney disease risk gene. Utilizing single-cell chromatin accessibility and CRISPR-based genome editing, we highlight GWAS variants that influenceTET2expression in kidney proximal tubule cells.

Experiments using kidney-tubule-specificTet2knockout mice indicated its protective role in cisplatin-induced acute kidney injury, as well as chronic kidney disease and fibrosis, induced by unilateral ureteral obstruction or adenine diet. Single-cell gene profiling of kidneys fromTet2knockout mice andTET2-knock-down tubule cells revealed the altered expression of DNA damage repair and chromosome segregation genes, notably includingINO80, another kidney function GWAS target gene itself.

Remarkably bothTET2-null andINO80-null cells exhibited an increased accumulation of micronuclei after injury, leading to the activation of cytosolic nucleotide sensor cGAS-STING. Genetic deletion of cGAS or STING in kidney tubules or pharmacological inhibition of STING protected TET2 null mice from disease development. In conclusion, our findings highlight TET2 and INO80 as key genes in the pathogenesis of kidney diseases, indicating the importance of DNA damage repair mechanisms.
DeepSLICEM: Clustering CryoEM particles using deep image and similarity graph representations
Authors: Palukuri Meghana V. , Marcotte Edward M.
Published: February 2024

Finding the 3D structure of proteins and their complexes has several applications, such as developing vaccines that target viral proteins effectively. Methods such as cryogenic electron microscopy (cryo-EM) have improved in their ability to capture high-resolution images, and when applied to a purified sample containing copies of a macromolecule, they can be used to produce a high-quality snapshot of different 2D orientations of the macromolecule, which can be combined to reconstruct its 3D structure. Instead of purifying a sample so that it contains only one macromolecule, a process that can be difficult, time-consuming, and expensive, a cell sample containing multiple particles can be photographed directly and separated into its constituent particles using computational methods.

Previous work, SLICEM, has separated 2D projection images of different particles into their respective groups using 2 methods, clustering a graph with edges weighted by pairwise similarities of common lines of the 2D projections. In this work, we develop DeepSLICEM, a pipeline that clusters rich representations of 2D projections, obtained by combining graphical features from a similarity graph based on common lines, with additional image features extracted from a convolutional neural network. DeepSLICEM explores 6 pretrained convolutional neural networks and one supervised Siamese CNN for image representation, 10 pretrained deep graph neural networks for similarity graph node representations, and 4 methods for clustering, along with 8 methods for directly clustering the similarity graph. On 6 synthetic and experimental datasets, the DeepSLICEM pipeline finds 92 method combinations achieving better clustering accuracy than previous methods from SLICEM. Thus, in this paper, we demonstrate that deep neural networks have great potential for accurately separating mixtures of 2D projections of different macromolecules computationally.
Building and analyzing metacells in single-cell genomics data
Authors: Bilous Mariia , Hérault Léonard , Gabriel Aurélie AG , Teleman Matei , Gfeller David
Published: February 2024

The advent of high-throughput single-cell genomics technologies has fundamentally transformed biological sciences. Currently, millions of cells from complex biological tissues can be phenotypically profiled across multiple modalities. The scaling of computational methods to analyze such data is a constant challenge and tools need to be regularly updated, if not redesigned, to cope with ever-growing numbers of cells. Over the last few years, metacells have been introduced to reduce the size and complexity of single-cell genomics data while preserving biologically relevant information. Here, we review recent studies that capitalize on the concept of metacells – and the many variants in nomenclature that have been used. We further outline how and when metacells should (or should not) be used to study single-cell genomics data and what should be considered when analyzing such data at the metacell level. To facilitate the exploration of metacells, we provide a comprehensive tutorial on construction and analysis of metacells from single-cell RNA-seq data (https://github.com/GfellerLab/MetacellAnalysisTutorial) as well as a fully integrated pipeline to rapidly build, visualize and evaluate metacells with different methods (https://github.com/GfellerLab/MetacellAnalysisToolkit).
Extrachromosomal DNA in cutaneous squamous cell carcinoma is associated with increased nodal disease
Authors: Bencomo Tomas , Thind Amarinder , Ashford Bruce , Ranson Marie , Lee Carolyn S.
Published: February 2024

Extrachromosomal DNA (ecDNA) is a mechanism of oncogene amplification that occurs in many cancers and has been linked to worse patient outcomes. While ecDNA has previously been identified in cutaneous melanoma, it has yet to be described in cutaneous squamous cell carcinoma (cSCC). Using whole genome sequencing and transcriptomic data of primary and metastatic cSCC tumors, we establish the presence of ecDNA in cSCC and confirm elevated expression of ecDNA-associated genes. We also find that the presence of ecDNA correlates with a higher lymph node ratio, a measure of disease severity. Together, these findings are the first to report ecDNA in cSCC and suggest that ecDNA gene amplifications promote an aggressive cSCC phenotype.
What is the correct genomic structure of the complex chromosomal rearrangement at theFmlocus in Silkie chicken?
Authors: Sharma Ashutosh , Vijay Nagarjun
Published: February 2024

ARISING FROM Zhu, F., Yin, ZT., Zhao, QS. et al. Communications Biologyhttps://doi.org/10.1038/s42003-023-05619-y(2023)

High-quality chromosome-level genome assemblies for numerous avian species promise to address longstanding questions in bird evolution and biology. In a recent issue ofCommunications Biology, Zhu, F., Yin, ZT., Zhao, QS. et al. (ZYZSJ)1presented a chromosome-level assembly for the Silkie chicken using a multi-platform high-coverage dataset to obtain accurate and complete sequences spanning the entire genome. A key finding from their genomic analysis is the reconstruction of the structure of the complex rearrangement at theFmlocus, the primary genetic change underlying the rare and conspicuous dermal hyperpigmentation phenotype generally called Fibromelanosis. However, in contrast to their identification of the*Fm_1scenario, several previously published studies2–6claim that*Fm_2is the valid scenario. Our re-analysis of ZYZSJ’s new assembly (CAU_Silkie) using long-read data from multiple black-bone chickens demonstrates that*Fm_2is the correct scenario. The*Fm_1scenario favoured by ZYZSJ results from an assembly error caused by mosaic haplotypes generated during the de novo assembly step. We recommend post-assembly validation and correction in genome projects to prevent misinterpretation due to assembly artefacts. Enhancing the assembly of haplotypes in such complex regions is essential for unravelling the genetic foundations of traits governed by genes within these areas.
Extensive novel diversity and phenotypic associations in the dromedary camel microbiome are revealed through deep metagenomics and machine learning
Authors: Mubaraki Fathi A
Published: February 2024

The dromedary camel, also known as one-humped camel or Arabian camel, is an iconic and economically important feature of Arabian society. Its contemporary importance in commerce and transportation, along with the historical and modern use of its milk and meat products for dietary health and wellness, make it an ideal subject of scientific scrutiny. The gut microbiome has recently been associated with numerous aspects of health, diet, lifestyle, and disease in livestock and humans alike, as well as serving as an exploratory and diagnostic marker of many physical characteristics. Our initial pilot analysis of 55 camel gut microbiomes from the Fathi Camel Microbiome Project using deep metagenomic shotgun sequencing reveals substantial novel species-level microbial diversity, for which we have generated an extensive catalog of prokaryotic metagenome-assembled microorganisms (MAGs) as a foundational microbial reference database for future comparative analysis. Exploratory correlation analysis exhibits substantial correlation structure among the collected subject-level metadata, including physical characteristics. Machine learning using these novel microbial markers, as well as statistical testing, demonstrates strong predictive performance of microbes to distinguish between multiple dietary and lifestyle characteristics in dromedary camels. We derive strongly predictive models for camel age, diet (including wheat), level of captivity. These findings and resources represent substantial strides toward understanding the camel microbiome and pave the way for a deeper understanding of the camel microbiome, as well as the nuanced factors that shape camel health.
A mathematical framework for understanding the spontaneous emergence of complexity applicable to growing multicellular systems
Authors: Zhang Lu , Xue Gang , Zhou Xiaolin , Huang Jiandong , Li Zhiyuan
Published: February 2024

In embryonic development and organogenesis, cells sharing identical genetic codes acquire diverse gene expression states in a highly reproducible spatial distribution, crucial for multicellular formation and quantifiable through positional information. To understand the spontaneous growth of complexity, we constructed a one-dimensional division-decision model, simulating the growth of cells with identical genetic networks from a single cell. Our findings highlight the pivotal role of cell division in providing positional cues, escorting the system toward states rich in information. Moreover, we pinpointed lateral inhibition as a critical mechanism translating spatial contacts into gene expression. Our model demonstrates that the spatial arrangement resulting from cell division, combined with cell lineages, imparts positional information, specifying multiple cell states with increased complexity—illustrated through examples inC.elegans. This study constitutes a foundational step in comprehending developmental intricacies, paving the way for future quantitative formulations to construct synthetic multicellular patterns.
Novel multi-omics deconfounding variational autoencoders can obtain meaningful disease subtyping
Authors: Li Zuqi , Katz Sonja , Saccenti Edoardo , Fardo David W. , Claes Peter , Martins dos Santos Vitor A.P. , Van Steen Kristel , Roshchupkin Gennady V.
Published: February 2024

Unsupervised learning, particularly clustering, plays a pivotal role in disease subtyp- ing and patient stratification, especially with the abundance of large-scale multi-omics data. Deep learning models, such as variational autoencoders (VAEs), can enhance clustering algorithms by leveraging inter-individual heterogeneity. However, the impact of confounders - external factors unrelated to the condition, e.g. batch effect or age - on clustering is often overlooked, introducing bias and spurious biological conclusions. In this work, we introduce four novel VAE-based deconfounding frameworks tailored for clustering multi-omics data. These frameworks effectively mitigate confounding effects while preserving genuine biological patterns. The deconfounding strategies employed include: i) removal of latent features correlated with confounders ii) a conditional variational autoencoder, iii) adversarial training, and iv) adding a regularization term to the loss function. Using real-life multi-omics data from TCGA, we simulated various confounding effects (linear, non-linear, categorical, mixed) and assessed model performance across 50 repetitions based on reconstruction error, clustering stability, and deconfounding efficacy. Our results demonstrate that our novel models, particularly the conditional multi-omics VAE (cXVAE), successfully handle simulated confounding effects and recover biologically-driven clustering structures. cXVAE accurately identifies patient labels and unveils meaningful pathological associations among cancer types, validating deconfounded representations. Furthermore, our study suggests that some of the proposed strategies, such as adversarial training, prove insufficient in confounder removal. In summary, our study contributes by proposing innovative frameworks for simultaneous multi-omics data integration, dimensionality reduction, and deconfounding in clustering. Benchmarking on open-access data offers guidance to end-users, facilitating meaningful patient stratification for optimized precision medicine.
Unlocking the secrets of kangaroo locomotor energetics: Postural adaptations underpin increased tendon stress in hopping kangaroos
Authors: Thornton Lauren H. , Dick Taylor J.M. , Hutchinson John R. , Lichtwark Glen A. , McGowan Craig P. , Rubenson Jonas , Wiktorowicz-Conroy Alexis , Clemente Christofer J.
Published: February 2024

Hopping kangaroos exhibit remarkably little change in their rate of metabolic energy expenditure with locomotor speed compared to other running animals. This phenomenon may be related to greater elastic energy savings due to increasing tendon stress; however, the mechanisms which enable the rise in stress remain poorly understood. In this study, we created a three-dimensional (3D) kangaroo musculoskeletal model, integrating 3D motion capture and force plate data, to analyse the kinematics and kinetics of hopping red and grey kangaroos. Using our model, we evaluated how body mass and speed influence (i) hindlimb posture, (ii) effective mechanical advantage (EMA), and (iii) the associated tendon stress in the ankle extensors and (iv) ankle work during hopping. We found that increasing ankle dorsiflexion and metatarsophalangeal plantarflexion likely played an important role in decreasing ankle EMA by altering both the muscle and external moment arms, which subsequently increased energy absorption and peak tendon stress at the ankle. Surprisingly, kangaroo hindlimb posture appeared to contribute to increased tendon stress, thereby elucidating a potential mechanism behind the increase in stress with speed. These posture-mediated increases in elastic energy savings could be a key factor enabling kangaroos to achieve energetic benefits at faster hopping speeds, but may limit the performance of large kangaroos due to the risk of tendon rupture.
A comparative study of circulating tumor cell isolation and enumeration technologies in lung cancer
Authors: Saini Volga M , Oner Ezgi , Ward Mark , Hurley Sinead , Henderson Brian David , Lewis Faye , Finn Stephen P , O’Leary John , O’Toole Sharon , O’Driscoll Lorraine , Gately Kathy
Published: February 2024

Circulating tumor cells (CTCs) have potential as diagnostic, prognostic and predictive biomarkers in solid tumors. Despite FDA approval of CTC devices in various cancers, their rarity and limited comparison between analysis methods hinder their clinical integration for lung cancer. This study aimed to evaluate five CTC isolation technologies using a standardized spike-in protocol: the CellMag™ (EpCAM-based enrichment), EasySep™ and RosetteSep™ (blood cell depletion), and the Parsortix® PR1 and next generation Parsortix® Plus (PX+) (size-based enrichment). The Parsortix® systems were also evaluated for any difference in recovery rates between cell harvest versus in- cassette staining. Healthy donor blood (5 mL) was spiked with 100 fluorescently labeled H1975 lung adenocarcinoma cell line, processed through each system and the isolation efficiency was calculated. All tested systems yielded discordant recovery rates with the CellMag™ having the highest mean recovery (70 ± 14%) followed by the PR1 (in-cassette staining) with a recovery of 49 ± 2% while the EasySep™ had the lowest recovery (18 ± 8%). The CellMag™ and Parsortix® PR1 may have potential clinical applications for lung cancer patients, albeit needing further optimization and validation.
Collective dynamical regimes predict invasion success and impacts in microbial communities
Authors: Hu Jiliang , Barbier Matthieu , Bunin Guy , Gore Jeff
Published: February 2024

Invasions of microbial communities by species such as pathogens can have significant impacts on ecosystem services and human health1–9. Predicting the outcomes of these invasions, however, remains a challenge. Various theories propose that these outcomes depend on either characteristics of the invading species10–12or attributes of the resident community13–16, including its composition and biodiversity3,17–19. Here we used a combination of experiments and theory to show that the interplay between dynamics, interaction strength, and diversity determine the invasion outcome in microbial communities. We found that the communities with fluctuations in species abundance are both more invasible and more diverse than stable communities, leading to a positive diversity-invasibility relationship among communities assembled in the same environment. As predicted by theory, increasing interspecies interaction strength and species pool size leads to a decrease of invasion probability in our experiment. Although diversity-invasibility relationships are qualitatively different depending upon how the diversity is changed, we provide a unified perspective on the diversity-invasibility debate by showing a universal positive correspondence between invasibility and survival fraction of resident species across all conditions. Communities composed of strongly interacting species can exhibit an emergent priority effect in which invader species are less likely to colonize than species in the original pool. However, in this regime of strong interspecies interactions, if an invasion is successful, it causes larger ecological effects on the resident community than when interactions are weak. Our results demonstrate that the invasibility and invasion effect are emergent properties of interacting species, which can be predicted by simple community-level features.
The molecular basis for functional divergence of duplicated SOX factors controlling endoderm formation and left-right patterning in zebrafish
Authors: Johal Simaran , Elsayed Randa , Panfilio Kristen A. , Nelson Andrew C.
Published: February 2024

Endoderm, one of three primary germ layers of vertebrate embryos, makes major contributions to the respiratory and gastrointestinal tracts and associated organs, including liver and pancreas. In mammals, the transcription factorSOX17is vital for endoderm organ formation and can induce endoderm progenitor identity. Duplication of ancestralsox17in the teleost lineage produced the paraloguessox32andsox17in zebrafish. Sox32 is required for specification of endoderm and progenitors of the left-right organiser (Kupffer’s Vesicle, KV), with Sox17 a downstream target of Sox32 that is implicated in further KV development. Phenotypic evidence therefore suggests functional similarities between zebrafish Sox32 and Sox17 and mammalian SOX17. Here, we directly compare these orthologues and paralogues, using the early zebrafish embryo as a biological platform for functional testing. Our results indicate that, unlike Sox32, human SOX17 cannot induce endoderm specification in zebrafish. Furthermore, using hybrid protein functional analyses, we show that Sox32 specificity for the endoderm gene regulatory network is linked to evolutionary divergence in its DNA-binding HMG domain from its paralogue Sox17. Additionally, changes in the C-terminal regions of Sox32 and Sox17 underpin their differing target specificities. Finally, we establish that specific conserved peptides in the C-terminal domain are essential for the role of Sox17 in establishing correct organ asymmetry. Overall, our results illuminate the molecular basis for functional divergence of Sox32 and Sox17 in vertebrate endoderm development and left-right patterning, and the evolution of SoxF transcription factor function.
How did vertebrate visual opsins diversify? - putting the last pieces of the puzzle together
Authors: Lagman David , Bergqvist Christina A. , Kuraku Shigehiro
Published: February 2024

A crucial event in the evolution of compex vertebrate vision was the expansion of the visual opsin family in the ancestral vertebrate. However, it has been controversial whether the expansion was achieved through whole genome duplications or in tandem gene duplications. We here performed a vertebrate-wide genome comparison, including jawless vertebrates, which strongly favors the latter scenario. Our analyses uncovered frequent paralogy underlying homologous phenotypes caused by massive gene losses and distinct paralog utilization between jawless and jawed vertebrates.
Optogenetic Regulation of EphA1 RTK Activation and Signaling
Authors: Wurz Anna I. , Zheng Kevin S. , Hughes Robert M.
Published: February 2024

Eph receptors are ubiquitous class of transmembrane receptors that mediate cell-cell communication, proliferation, differentiation, and migration. EphA1 receptors specifically play an important role in angiogenesis, fetal development, and cancer progression; however, studies of this receptor can be challenging as its ligand, ephrinA1, binds and activates several EphA receptors simultaneously. Optogenetic strategies could be applied to circumvent this requirement for ligand activation and enable selective activation of the EphA1 subtype. In this work, we designed and tested several iterations of an optogenetic EphA1 - Cryptochrome 2 (Cry2) fusion, investigating their capacity to mimic EphA1-dependent signaling in response to light activation. We then characterized the key cell signaling target of MAPK phosphorylation activated in response to light stimulation. The optogenetic regulation of Eph receptor RTK signaling without the need for external stimulus promises to be an effective means of controlling individual Eph receptor-mediated activities and creates a path forward for the identification of new Eph-dependent functions.
Diversity, Origin and Evolution of the ESCRT Systems
Authors: Makarova Kira S. , Tobiasson Victor , Wolf Yuri I. , Lu Zhongyi , Liu Yang , Zhang Siyu , Krupovic Mart , Li Meng , Koonin Eugene V
Published: February 2024

Endosomal Sorting Complexes Required for Transport (ESCRT) play key roles in protein sorting between membrane-bounded compartments of eukaryotic cells. Homologs of many ESCRT components are identifiable in various groups of archaea, especially in Asgardarchaeota, the archaeal phylum that is currently considered to include the closest relatives of eukaryotes, but not in bacteria. We performed a comprehensive search for ESCRT protein homologs in archaea and reconstructed ESCRT evolution using the phylogenetic tree of Vps4 ATPase (ESCRT IV) as a scaffold, using sensitive protein sequence analysis and comparison of structural models to identify previously unknown ESCRT proteins. Several distinct groups of ESCRT systems in archaea outside of Asgard were identified, including proteins structurally similar to ESCRT-I and ESCRT-II, and several other domains involved in protein sorting in eukaryotes, suggesting an early origin of these components. Additionally, distant homologs of CdvA proteins were identified in Thermoproteales which are likely components of the uncharacterized cell division system in these archaea. We propose an evolutionary scenario for the origin of eukaryotic and Asgard ESCRT complexes from ancestral building blocks, namely, the Vps4 ATPase, ESCRT-III components, wH (winged helix-turn-helix fold) and possibly also coiled-coil, and Vps28-like domains. The Last Archaeal Common Ancestor likely encompassed a complex ESCRT system that was involved in protein sorting. Subsequent evolution involved either simplification, as in the TACK superphylum, where ESCRT was co-opted for cell division, or complexification as in Asgardarchaeota. In Asgardarchaeota, the connection between ESCRT and the ubiquitin system that was previously considered a eukaryotic signature was already established.

Importance

All eukaryotic cells possess complex intracellular membrane organization. ESCRT (Endosomal Sorting Complexes Required for Transport) plays a central role in membrane remodeling which is essential for cellular functionality in eukaryotes. Recently, it has been shown that Asgard archaea, the archaeal phylum that includes the closest known relatives of eukaryotes, encode homologs of many components of the ESCRT systems. We employed protein sequence and structure comparisons to reconstruct the evolution of ESCRT systems in archaea and identified several previously unknown homologs of ESCRT subunits, some of which can be predicted to participate in cell division. The results of this reconstruction indicate that the Last Archaeal Common ancestor already encoded a complex ESCRT system that was involved in protein sorting. In Asgard archaea, ESCRT systems evolved towards greater complexity, and in particular, the connection between ESCRT and the ubiquitin system that was previously considered a eukaryotic signature was established.
Standard rodent diets differentially impact alcohol consumption and preference and gut microbiome diversity
Authors: Zaparte Aline , Dore Evan , White Selby , Paliarin Franciely , Gabriel Cameron , Copenhaver Katherine , Basavanhalli Samhita , Garcia Emily , Vaddavalli Rishith , Luo Meng , Taylor Christopher M. , Welsh David , Maiya Rajani
Published: February 2024

Alcohol Use Disorder (AUD) is a complex and widespread disease with limited pharmacotherapies. Preclinical animal models of AUD use a variety of voluntary alcohol consumption procedures to recapitulate different phases of AUD including binge alcohol consumption and dependence. However, voluntary alcohol consumption in mice is widely variable rendering it difficult to reproduce results across labs. Accumulating evidence indicates that different brands of commercially available rodent chow can profoundly influence alcohol intake. In this study, we investigated the effects of three commercially available and widely used rodent diet formulations on alcohol consumption and preference in C57BL/6J mice using the 24h intermittent access procedure. The three brands of chow tested were LabDiet 5001 (LD 5001), LabDiet 5053 (LD 5053), and Teklad 2019S (TL2019S) from two companies (Research Diets and Envigo respectively). Mice fed LD5001 displayed the highest levels of alcohol consumption and preference followed by LD5053 and TL2019S. We also found that alcohol consumption and preference could be rapidly switched by changing the diet 48h prior to alcohol administration. Sucrose, saccharin, and quinine preference were not altered suggesting that the diets did not alter taste perception. We also found that mice fed LD5001 displayed increased quinine-resistant alcohol intake compared to mice fed TL2019S, suggesting that diets could influence the development of “compulsive” like alcohol consumption. We profiled the gut microbiome of water and alcohol drinking mice that were maintained on different diets and found significant differences in bacterial alpha and beta diversity, which could impact gut-brain axis signaling and alcohol consumption.
The association of lifestyle with cardiovascular and all-cause mortality based on machine learning: A Prospective Study from the NHANES
Authors: Guo Xinghong , Wu Jian , Ma Mingze , Tarimo Clifford Silver , Fei Fengyi , Zhao Lipei , Ye Beizhu
Published: February 2024

Objective

To develop a machine learning (ML) risk stratification model for predicting all-cause mortality and cardiovascular mortality while estimating the influence of lifestyle behavioral factors on the model’s efficacy.

Method

A prospective cohort study was conducted using a nationally representative sample of adults aged 40 years or older, drawn from the US National Health and Nutrition Examination Survey from 2007 to 2010. The participants underwent a comprehensive in-person interview and medical laboratory examinations, and subsequently, their records were linked with the National Death Index for further analysis.

Result

Within a cohort comprising 7921 participants, spanning an average follow-up duration of 9.75 years, a total of 1911 deaths, including 585 cardiovascular-related deaths, were recorded. The model predicted mortality with an area under the receiver operating characteristic curve (AUC) of 0.848 and 0.829. Stratifying participants into distinct risk groups based on ML scores proved effective. All lifestyle behaviors exhibited an inverse association with all-cause and cardiovascular mortality. As age increases, the discernible impacts of dietary scores and sedentary time become increasingly apparent, whereas an opposite trend was observed for physical activity.

Conclusion

We develop a ML model based on lifestyle behaviors to predict all-cause and cardiovascular mortality. The developed model offers valuable insights for the assessment of individual lifestyle-related risks. It applies to individuals, healthcare professionals, and policymakers to make informed decisions.
Effects of intervention stage completion in an integrated behavioral health and primary care randomized pragmatic intervention trial
Authors: Stephens Kari A. , van Eeghen Constance , Zheng Zihan , Anastas Tracy , Ma Kris Pui Kwan , Prado Maria G. , Clifton Jessica , Rose Gail , Mullin Daniel , Chan Kwun C. G. , Kessler Rodger
Published: February 2024

Purpose

A pragmatic, cluster-randomized controlled trial of a comprehensive practice-level, multi-staged practice transformation intervention aimed to increase behavioral health integration in primary care practices and improve patient outcomes. We examined association between the completion of intervention stages and patient outcomes across a heterogenous national sample of primary care practices.

Methods

Forty-two primary care practices across the U.S. with co-located behavioral health and 2,426 patients with multiple chronic medical and behavioral health conditions completed surveys at baseline, midpoint and two year follow-up. Effects of the intervention on patient health and primary care integration outcomes were examined using multilevel mixed-effects models, while controlling for baseline outcome measurements.

Results

No differences were found associated with the number of intervention stages completed in patient health outcomes were found for depression, anxiety, fatigue, sleep disturbance, pain, pain interference, social function, patient satisfaction with care or medication adherence. The completion of each intervention stage was associated with increases in Practice Integration Profile (PIP) domain scores and were confirmed with modeling using multiple imputation for: Workflow 3.5 (95% CI: 0.9-6.1), Integration Methods 4.6 (95% CI: 1.5-7.6), Patient Identification 2.9 (95% CI: 0.9-5.0), and Total Integration 2.7 (95% CI: 0.7-4.7).

Conclusion

A practice-centric flexible practice transformation intervention improved integration of behavioral health in primary care across heterogenous primary care practices treating patients with multiple chronic conditions. Interventions that allow practices to flexibly improve care have potential to help complex patient populations. Future research is needed to determine how to best target patient health outcomes at a population level.
Neurotensin-Neurotensin Receptor 2 signaling in adipocytes regulates food intake through ceramide metabolism
Authors: Fu Wei , Yang Yue , Guo Xiao , Gong Qifan , Zhou Xiaofeng , Zhou Liying , Liu Cenxi , Zhang Zhi , So Jisun , Zhang Yufeng , Huang Lin , Lu Guangxing , Yi Chuanyou , Wang Qichu , Fan Chenyu , Liu Chao , Wang Jiaxing , Yu Haiyi , Zhao Yimin , Huang Tao , Roh Hyun Cheol , Liu Tiemin , Tang Huiru , Qi Jianping , Xu Ming , Zheng Yan , Huang He , Li Jin
Published: February 2024

Neurotensin (NTS) is a secretory peptide produced by the lymphatic endothelial cells (LEC). Our previous study revealed that NTS suppressed the activity of brown adipose tissue via the interactions with NTSR2. In the current study, we found that the depletion ofNtsr2in the white adipocytes upregulated food intake, while the local treatment of NTS suppressed the food intake. Mechanistic study revealed that the suppression of NTS-NTSR2 signaling enhanced the phosphorylation of ceramide synthetase 2 (CerS2), increased the abundance of its products ceramide C20-C24 and downregulated the production of GDF15 in the white adipose tissues, which was responsible for the elevation of food intake. With four populations of different age and ethnic background, we discovered a potential causal and positive correlation between ceramide C20-24 and food intake in human. Our study identified that NTS-NTSR2 signaling can perform the neurological regulation via controlling the production of ceramide in the white adipocytes.
Telephone training to improve ECG quality in remote screening for atrial fibrillation
Authors: Bhayankaram Kethaki Prathivadi , Mant Jonathan , Brimicombe James , Dymond Andrew , Williams Kate , Charlton Peter H.
Published: February 2024

Background and Aims

Self-recorded, single-lead ECGs are increasingly used to diagnose arrhythmias. However, they can be of variable quality, which can affect the reliability of interpretation. In this analysis of ECGs collected in atrial fibrillation screening studies, our aims were to: (i) determine the quality of ECGs when recorded unsupervised (at home); and (ii) investigate whether telephone training improved ECG quality.

Methods

Data was obtained from the Screening for Atrial Fibrillation to Reduce stroke (SAFER) programme, where participants recorded single-lead ECGs four times per day for three weeks using a handheld device. ECG quality was assessed using an automated algorithm, and participants who recorded >25% poor quality ECGs from days 4-10 of screening were identified for training. Telephone training to improve ECG recording technique was delivered when research team capacity permitted.

Results

14,727 participants recorded 1,206,972 ECGs, of which 43,513 (3.6%) were poor quality. Most participants (51.9%) did not record any poor-quality ECGs. 1,105 (7.5%) participants met the threshold for training. Of these, 165 participants received training and 896 did not. Comparing these groups, the mean (95% confidence interval) reduction in the proportion of poor-quality ECGs per participant from before training (days 1-3) to after training (days 11-21) was 21.1 (17.5-23.5) % with training and 15.7 (14.5-16.8) % without training (p<0.05).

Conclusion

Most participants achieved adequate quality ECGs. For those that did not, ECG quality improved over time regardless, and training further improved ECG quality. Therefore, telephone training could be considered in atrial fibrillation screening programmes using single-lead ECG devices.

What’s new?

- This is the first study to explore telephone training as a way to improve the quality of ECGs.

- We found that the quality of ECGs recorded by participants increased naturally over time, regardless of whether they received telephone training. A minimum time period of screening is required to allow for this natural improvement in quality.

- Telephone training was found to be beneficial in improving ECG quality, and was associated with greater improvement in quality than due to natural improvement alone.

- Real-time transmission of ECGs and assessment of ECG quality may be useful to identify participants who may benefit from telephone training.

- The quality of ECGs obtained at home is comparable when using an entirely remote process (postal device delivery and optional telephone training) vs. using an initial face-to-face training session (in-person device setup and training from GP practice nurses).
A novel ilarvirus protein CP-RT is expressed via stop codon readthrough and suppresses RDR6-dependent RNA silencing
Authors: Lukhovitskaya Nina , Brown Katherine , Hua Lei , Pate Adrienne E. , Carr John P. , Firth Andrew E.
Published: February 2024

Ilarviruses are a relatively understudied but important group of plant RNA viruses that includes a number of crop pathogens. Their genomes comprise three RNA segments encoding two replicase subunits, movement protein, coat protein (CP), and (in some ilarvirus subgroups) a protein that suppresses RNA silencing. Here we report that, in many ilarviruses, RNA3 encodes an additional protein (termed CP-RT) as a result of ribosomal readthrough of the CP stop codon into a short downstream readthrough (RT) ORF. Using asparagus virus 2 as a model, we find that CP-RT is expressedin plantawhere it functions as a weak suppressor of RNA silencing. CP-RT expression is essential for persistent systemic infection in leaves and shoot apical meristem. CP-RT function is dependent on a putative zinc-finger motif within RT. Replacing the asparagus virus 2 RT with the RT of an ilarvirus from a different subgroup restored the ability to establish persistent infection. These findings open up a new avenue for research on ilarvirus silencing suppression, persistent meristem invasion and vertical transmission.