bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphologic Features in Congenital Pulmonary Airway Malformations and Pulmonary Sequestrations Correlate With Mutation Status
Authors: Nelson Nya D. , Xu Feng , Peranteau William H. , Li Marilyn , Pogoriler Jennifer
Published: February 2023

Congenital pulmonary airway malformations (CPAMs) have a range of morphologies with varying cyst sizes and histologic features (types 1 to 3). Evidence suggested they arise secondary to bronchial atresia, however, we recently showed that cases with type 1 and 3 morphology are driven by mosaic KRAS mutations. We hypothesized that 2 distinct mechanisms account for most CPAMs: one subset is secondary to KRAS mosaicism and another is due to bronchial atresia. Cases with type 2 histology, similar to sequestrations, would be related to obstruction and therefore negative for KRAS mutations regardless of cyst size. We sequenced KRAS exon 2 in type 2 CPAMs, cystic intralobar and extralobar sequestrations, and intrapulmonary bronchogenic cysts. All were negative. Most sequestrations had a large airway in the subpleural parenchyma adjacent to the systemic vessel, anatomically confirming bronchial obstruction. We compared morphology to type 1 and 3 CPAMs. On average, type 1 CPAMs had significantly larger cysts, but there remained substantial size overlap between KRAS mutant and wild-type lesions. Features of mucostasis were frequent in sequestrations and type 2 CPAMs, while their cysts were generally simple and round with flat epithelium. Features of cyst architectural and epithelial complexity were more common in type 1 and 3 CPAMs, which rarely showed mucostasis. Similarity in histologic features among cases that are negative for KRAS mutation support the hypothesis that, like sequestrations, the malformation of type 2 CPAMs is related to obstruction during development. A mechanistic approach to classification may improve existing subjective morphologic methods.
The Ratio of Clavicle Length to Head Circumference
Authors: Huang Shu-Jing , Huang Mei , Liu Xian-Lan , Hong Long-Cheng , Su Yu-Qing , Lin Yan-Ting , Wang Yan-Qing , Lin Jin-Rong , Zhang Xiao-Dong , Zhou Ying , Su Yi-Ming
Published: February 2023

We aimed to plot the growth curve of the fetal clavicle, identify gestational date-independent parameters. Using 2-dimensional ultrasonography, we obtained the clavicle lengths (CLs) from 601 normal fetuses between 12 and 40 gestational age (GA). The CL/fetal growth parameters ratio was calculated. Moreover, 27 cases of fetal growth restriction (FGR) and 9 cases of small for GA (SGA) were detected. In normal fetuses, the mean CL (mm) = −68.2 + 29.80 × ln(GA) ± Z × (1.07 + 0.02 × GA). A linear relationship was detected between CL and head circumference (HC), biparietal diameter, abdominal circumference and femoral length with R
2 values of 0.973, 0.970, 0.962, and 0.972, respectively. The CL/HC ratio (mean value 0.130) showed no significant correlation with GA. Clavicle lengths in the FGR group significantly decreased compared with the SGA group (P < 0.01). This study determined a reference range of fetal CL in a Chinese population. Furthermore, the CL/HC ratio, which is independent of GA, is a novel parameter for the evaluation of the fetal clavicle.
OUTCOMES FOLLOWING ZONE 3 AND ZONE 1 AORTIC OCCLUSION FOR THE TREATMENT OF BLUNT PELVIC INJURIES
Authors: Cralley Alexis L. , Moore Ernest E. , Dubose Joseph , Brenner Megan L. , Schaid Terry R. , DeBot Margot , Cohen Mitchell , Silliman Christopher , Fox Charles , Sauaia Angela
Published: February 2023

Background: A 2021 report of the Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery multicenter registry described the outcomes of patients treated with Zone 3 resuscitative endovascular balloon occlusion of the aorta (REBOA zone 3). Our study builds upon that report, testing the hypothesis that REBOA zone 3 is associated with better outcomes than REBOA Zone 1 in the immediate treatment of severe, blunt pelvic injuries. Methods: We included adults who underwent aortic occlusion (AO) via REBOA zone 1 or REBOA Zone 3 in the emergency department for severe, blunt pelvic injuries [Abbreviated Injury Score ≥ 3 or pelvic packing/embolization/first 24 hours] in institutions with >10 REBOAs. Adjustment for confounders was accomplished with a Cox proportional hazards model for survival, generalized estimating equations for intensive care unit (ICU)-free days (IFD) and ventilation-free days (VFD) > 0 days, and mixed linear models for continuous outcomes (Glasgow Coma Scale [GCS], Glasgow Outcome Scale [GOS]), accounting for facility clustering. Results: Of 109 eligible patients, 66 (60.6%) underwent REBOA Zone 3 and 43 (39.4%) REBOA Zone 1. There were no differences in demographics, but compared with REBOA Zone 3, REBOA Zone 1 patients were more likely to be admitted to high volume centers and be more severely injured. These patients did not differ in systolic blood pressure (SBP), cardiopulmonary resuscitation in the prehospital/hospital settings, SBP at the start of AO, time to AO start, likelihood of achieving hemodynamic stability or requirement of a second AO. After controlling for confounders, compared with REBOA Zone 3, REBOA Zone 1 was associated with a significantly higher mortality (adjusted hazard ratio, 1.51; 95% confidence interval [CI], 1.04–2.19), but there were no differences in VFD > 0 (adjusted relative risk, 0.66; 95% CI, 0.33–1.31), IFD > 0 (adjusted relative risk, 0.78; 95% CI, 0.39–1.57), discharge GCS (adjusted difference, −1.16; 95% CI, −4.2 to 1.90) or discharge GOS (adjusted difference, −0.67; 95% CI −1.9 to 0.63). Conclusions: This study suggests that compared with REBOA Zone 1, REBOA Zone 3 provides superior survival and is not inferior regarding other adverse outcomes in patients with severe blunt pelvic injuries.
Evaluation of five commercial DNA extraction kits using Salmonella as a model for implementation of rapid Nanopore sequencing in routine diagnostic laboratories
Authors: Eagle Shannon H. C. , Robertson James , Bastedo D. Patrick , Liu Kira , Nash John H. E.
Published: February 2023

Oxford Nanopore long-read sequencing offers advantages over Illumina short reads for the identification and characterization of bacterial pathogens for outbreak detection and surveillance activities within a diagnostic public health laboratory context. Compared to Illumina, Nanopore is more cost-effective for small batches, has a lower capital cost and has a faster turnaround time, in addition to the ability to assemble complete bacterial genomes. The quantity and quality of DNA required for Nanopore sequencing are greater than for Illumina, and the DNA extraction methods recommended for obtaining high-molecular-weight DNA are different from those typically used in diagnostic laboratories. Using a

Salmonella

isolate with a previously closed PacBio genome as a model Enterobacteriaceae organism, we evaluated the quantity, quality and fragmentation of five commercial DNA extraction kits. Nanopore sequencing performance was evaluated for the top three methods: Qiagen EZ1 DNA Tissue, Qiagen DNeasy Blood and Tissue, and a modified, in-house version of the MasterPure Complete DNA and RNA purification. To evaluate the effect of post-extraction DNA purification methods, we subjected extracted DNA from the three selected extraction methods to purification by AMPure beads or ethanol precipitation and compared these outputs with untreated DNA as a control. All methods are suitable for routine whole-genome sequencing (WGS), since all 60 replicates had very high genome recovery rates, with ≥98 % of the reference genome covered by mapped Nanopore reads. For 85 % of the replicates, assembly was able to produce a complete, circular chromosome using either Flye or Canu. In most cases, it is recommended to move directly from extraction to sequencing, as untreated DNA had the highest rates of genome closure regardless of extraction method. Using our evaluation criteria, the Qiagen DNeasy Blood and Tissue kit was found to be the best overall method due to its low cost, ability to scale from single tubes to 96-well plates, and high consistency in yield and sequencing performance.
Inter-species diversity and functional genomic analyses of closed genome assemblies of clinically isolated, megaplasmid-containing Enterococcus raffinosus Er676 and ATCC49464
Authors: Sharon Belle M. , Hulyalkar Neha V. , Zimmern Philippe E. , Palmer Kelli L. , De Nisco Nicole J.
Published: February 2023

Enterococcus raffinosus is an understudied member of its genus possessing a characteristic megaplasmid contributing to a large genome size. Although less commonly associated with human infection compared to other enterococci, this species can cause disease and persist in diverse niches such as gut, urinary tract, blood, and environment. Few complete genome assemblies have been published to date for E. raffinosus. In this study, we report the complete assembly of the first clinical urinary E. raffinosus strain, Er676, isolated from a postmenopausal woman with history of recurrent urinary tract infection (rUTI). We additionally completed the assembly of clinical type strain ATCC49464. Comparative genomic analyses reveal inter-species diversity driven by large accessory genomes. The presence of a conserved megaplasmid indicates it is a ubiquitous and vital genetic feature of E. raffinosus. We find that the E. raffinosus chromosome is enriched for DNA replication and protein biosynthesis genes while the megaplasmid is enriched for transcription and carbohydrate metabolism genes. Prophage analysis suggests that diversity in the chromosome and megaplasmid sequences arises, in part, from horizontal gene transfer. Er676 demonstrated the largest genome size reported to date of E. raffinosus and the highest probability of human pathogenicity. Er676 also possesses multiple antimicrobial resistance genes (ARGs), of which all but one are encoded on the chromosome, and has the most complete prophage sequences. Complete assembly and comparative analyses of the Er676 and ATCC49464 genomes provide important insight into the inter-species diversity of E. raffinosus that enables its ability to colonize and persist in the human body. Investigating genetic factors that contribute to this species pathogenicity will lend valuable tools to combat diseases caused by this opportunistic pathogen.
Using human genetics to validate complement C3 as a drug target in periodontitis
Authors: Alayash Zoheir , Baumeister Sebastian-Edgar , Holtfreter Birte , Kocher Thomas , Baurecht Hansjörg , Ehmke Benjamin , Nolde Michael , Reckelkamm Stefan Lars
Published: February 2023

Aim

Evidence from a phase IIa trial showed that a complement C3-targeted drug reduced gingival inflammation in patients with gingivitis. We investigated the therapeutic effect of genetically proxied C3 inhibition on periodontitis using drug target Mendelian randomization (MR).

Materials and methods

We used multiple ‘cis’ instruments from the vicinity of the encoding loci of C3 that are associated with serum C3. We selected three independent single nucleotide polymorphisms (rs141552034, rs145406915, rs11569479) from a genome-wide association study (GWAS) of 5,368 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse-variance weighted meta-analysis.

Results

MR analysis revealed that the inhibition of C3 reduces the risk of periodontitis (Odds ratio 0.91 per 1 standard deviation reduction in C3; 95% Confidence Interval 0.87–0.96, P-value=0.0003).

Conclusions

Findings from MR analysis showed that C3 blockade protects against periodontitis.

Clinical relevance

Scientific rationale for study

Mounting evidence suggests that the complement system is dysregulated in periodontitis. First human randomized clinical trials demonstrated promising effects mediated via the blockade of C3, a key factor of the complement system. Results from drug target MR analysis can provide compelling evidence to predict the efficacy of pharmacological C3 blockage in future clinical trials in periodontitis patients.

Principle findings

Genetically proxied C3 inhibition reduced periodontitis risk.

Practical implications

Our MR analysis provides genetic evidence that C3-targeted drugs might be an efficient adjunct therapy in periodontitis.
A third vaccine dose equalizes the levels of effectiveness and immunogenicity of heterologous or homologous COVID-19 vaccine regimens
Authors: Guibert Nicolas , Trepat Kylian , Pozzetto Bruno , Josset Laurence , Fassier Jean-Baptiste , Allatif Omran , Saker Kahina , Brengel-Pesce Karen , Walzer Thierry , Vanhems Philippe , Trouillet-Assant Sophie
Published: February 2023

Backgroung

To cope with the persistence of the Covid-19 epidemic and the decrease in antibody levels following vaccination, a third dose of vaccine has been recommended in the general population. However, several vaccine regimens had been used initially, and the heterologous ChadOx1-S/BNT162b2 regimen had shown better efficacy and immunogenicity than the homologous BNT162b2/BNT162b2 regimen.

Aim

We wanted to determine if this benefit was retained after the third dose.

Methods

We combined an observational study of SARS-COV-2 infections among vaccinated healthcare workers at the University-Hospital of Lyon, France, with an analysis of immunological parameters before and after the third mRNA vaccine dose.

Results

Following the second vaccine dose, heterologous vaccination regimens were more protective against infection than homologous regimens, but this was no longer the case after the third dose. RBD-specific IgG levels and serum neutralization capacity against different SARS-CoV-2 variants were higher after the third dose than after the second dose in the homologous regimen group, but not in the heterologous group.

Conclusion

The advantage conferred by heterologous vaccination is lost after the third dose both in terms of protection and immunogenicity. Immunological measurements suggest that heterologous vaccination induces maximal immunity after the second dose, whereas the third dose is required to reach the same level in individuals with a homologous regimen.
Relationship between adherence to the 2019 Canada’s Food Guide recommendations on healthy food choices and nutrient intakes in older adults
Authors: Brassard Didier , Chevalier Stéphanie
Published: February 2023

Background

Following Canada’s food guide (CFG) recommendations should ensure adequate nutrient intakes. Older adults have increased needs for certain nutrients and nutrient density; the extent to which adherence to CFG recommendations can help reduce inadequate nutrient intakes is unknown.

Objective

Our aim was to assess the relationship between adherence to CFG recommendations on healthy food choices and intake of key nutrients in adults 65 years and older from the Canadian Community Health Survey (CCHS) 2015 - Nutrition.

Methods

Secondary analysis of data from 4,093 older adults of the CCHS 2015 - Nutrition (mean age, 73.6 years, 54% females). Dietary intakes were measured using an interviewer-administered 24-hour dietary recall including one repeat in a subsample (42%). The National Cancer Institute multivariate method was used to estimate usual (i.e., long-term) dietary intakes. Adherence to CFG recommendations was measured using the Healthy Eating Food Index (HEFI)-2019 score. Simple linear and logistic regression models estimated the effect of increased HEFI-2019 score on usual nutrient intakes and the prevalence of inadequate nutrient intakes (i.e., below the estimated average requirements), respectively.

Results

Compared with the prevalence of inadequate intakes at median HEFI-2019 score (46.4/80 points), a higher HEFI-2019 (+11 points) was associated with reductions in the prevalence of inadequate intakes of magnesium, vitamin B6, and protein (-19.8% [95%CI: -30.8, -8.9], -12.7% [95%CI: -22.5, -3.0], and -4.7% [95%CI: -9.4, -0.1], respectively). In contrast, data for higher HEFI-2019 scores were compatible with increased prevalence of inadequate intakes of folate, vitamin D, and calcium (4.0% [95%CI: -8.4, 16.3], 2.6% [95%CI: 1.1, 4.0], and 2.3% [95%CI: -3.0, 7.5], respectively).

Conclusions

Based on dietary intakes of Canadian older adults in 2015, increasing the degree of adherence to CFG recommendations on healthy food choices may reduce nutrient intake inadequacy for most key nutrients except folate, vitamin D and calcium.
Interpreting biologically informed neural networks for enhanced biomarker discovery and pathway analysis
Authors: Hartman Erik , Scott Aaron , Malmström Lars , Malmström Johan
Published: February 2023

The advent of novel methods in mass spectrometry-based proteomics allows for the identification of biomarkers and biological pathways which are crucial for the understanding of complex diseases. However, contemporary analytical methods often omit essential information, such as protein abundance and protein co-regulation, and therefore miss crucial relationships in the data. Here, we introduce a generalized workflow that incorporates proteins, their abundances, and associated pathways into a deep learning-based methodology to improve biomarker identification and pathway analysis through the creation and interpretation of biologically informed neural networks (BINNs). We successfully employ BINNs to differentiate between two subphenotypes of septic acute kidney injury (AKI) and COVID-19 from the plasma proteome and utilize feature attribution-methods to introspect the networks to identify which proteins and pathways are important for distinguishing between subphenotypes. Compared to existing methods, BINNs achieved the highest predictive accuracy and revealed that metabolic processes were key to differentiating between septic AKI subphenotypes, while the immune system was more important to the classification of COVID-19 subphenotypes. The methodology behind creating, interpreting, and visualizing BINNs were implemented in a free and open source Python-package:https://github.com/InfectionMedicineProteomics/BINN.
Communicating the benefits of quitting smoking on mental health increases motivation to quit in people with anxiety and/or depression: A randomized trial of two health messages
Authors: Steinberg Marc L. , Rosen Rachel L. , Ganz Ollie , Wackowski Olivia A. , Jeong Michelle , Delnevo Cristine D.
Published: February 2023

Background

Although smoking rates have declined over time, this decline has not been observed among those with mental health concerns. It is therefore important to develop effective messaging to support quitting in this population.

Methods

We conducted an online experiment with 419 adults who smoke cigarettes daily. Participants with, or without a lifetime history of anxiety and/or depression were randomized to view a message focused on the benefits of quitting smoking on mental or physical health. Participants then reported motivation to quit smoking, mental health concerns about quitting, and perceived effectiveness of the message.

Results

Participants with a lifetime history of anxiety and/or depression who saw the message focused on the benefits of quitting smoking on mental health reported greater motivation to quit than when they saw a message focused on the benefits to physical health. This was not replicated when examining current symptoms instead of lifetime history. Pre-existing beliefs that smoking improves one’s mood were greater in those experiencing current symptoms and in those with a lifetime history of anxiety and/or depression. There was no main or interaction (message type X mental health status) effect of message type received on mental health related concerns about quitting.

Conclusions

This study is one of the first to evaluate a smoking cessation message with content specifically targeted to those with mental health concerns about quitting smoking. Additional work is needed to determine how to best target those with mental health concerns with messages focused on the benefits of quitting on mental health.

Implications

These data can begin to inform regulatory efforts to address tobacco use in those with comorbid anxiety and/or depression by providing information on how to effectively communicate the benefits of quitting smoking on mental health.
An SEIDR Model for the Early Spread of COVID-19
Authors: Cao Tingrui
Published: February 2023

In this article, we conduct a literature review on the history and mathematical modeling of infectious diseases and COVID-19. Next, some simple epidemic dynamic models and the basic reproductive number theory are introduced. We propose a SEIDR model for COVID-19 and provide the solution methods for the basic reproduction number, parameters, and dynamic model. Finally, we simulate the early stages of the COVID-19 epidemic in Argentina, Indonesia, Mexico, and South Africa with the SEIDR model.
OME-Zarr: a cloud-optimized bioimaging file format with international community support
Authors: Moore Josh , Basurto-Lozada Daniela , Besson Sébastien , Bogovic John , Bragantini Jordão , Brown Eva M. , Burel Jean-Marie , Casas Moreno Xavier , de Medeiros Gustavo , Diel Erin E. , Gault David , Ghosh Satrajit S. , Gold Ilan , Halchenko Yaroslav O. , Hartley Matthew , Horsfall Dave , Keller Mark S. , Kittisopikul Mark , Kovacs Gabor , Küpcü Yoldaş Aybüke , Kyoda Koji , le Tournoulx de la Villegeorges Albane , Li Tong , Liberali Prisca , Lindner Dominik , Linkert Melissa , Lüthi Joel , Maitin-Shepard Jeremy , Manz Trevor , Marconato Luca , McCormick Matthew , Lange Merlin , Mohamed Khaled , Moore William , Norlin Nils , Ouyang Wei , Özdemir Bugra , Palla Giovanni , Pape Constantin , Pelkmans Lucas , Pietzsch Tobias , Preibisch Stephan , Prete Martin , Rzepka Norman , Samee Sameeul , Schaub Nicholas , Sidky Hythem , Solak Ahmet Can , Stirling David R. , Striebel Jonathan , Tischer Christian , Toloudis Daniel , Virshup Isaac , Walczysko Petr , Watson Alan M. , Weisbart Erin , Wong Frances , Yamauchi Kevin A. , Bayraktar Omer , Cimini Beth A. , Gehlenborg Nils , Haniffa Muzlifah , Hotaling Nathan , Onami Shuichi , Royer Loic A. , Saalfeld Stephan , Stegle Oliver , Theis Fabian J. , Swedlow Jason R.
Published: February 2023

A growing community is constructing a next-generation file format (NGFF) for bioimaging to overcome problems of scalability and heterogeneity. Organized by the Open Microscopy Environment (OME), individuals and institutes across diverse modalities facing these problems have designed a format specification process (OME-NGFF) to address these needs. This paper brings together a wide range of those community members to describe the cloud-optimized format itself – OME-Zarr – along with tools and data resources available today to increase FAIR access and remove barriers in the scientific process. The current momentum offers an opportunity to unify a key component of the bioimaging domain — the file format that underlies so many personal, institutional, and global data management and analysis tasks.
Active mesh and neural network pipeline for cell aggregate segmentation
Authors: Smith Matthew B. , Sparks Hugh , Almagro Jorge , Chaigne Agathe , Behrens Axel , Dunsby Chris , Salbreux Guillaume
Published: February 2023

Segmenting cells within cellular aggregates in 3D is a growing challenge in cell biology, due to improvements in capacity and accuracy of microscopy techniques. Here we describe a pipeline to segment images of cell aggregates in 3D. The pipeline combines neural network segmentations with active meshes. We apply our segmentation method to cultured mouse mammary duct organoids imaged over 24 hours with oblique plane microscopy, a high-throughput light-sheet fluorescence microscopy technique. We show that our method can also be applied to images of mouse embryonic stem cells imaged with a spinning disc microscope. We segment individual cells based on nuclei and cell membrane fluorescent markers, and track cells over time. We describe metrics to quantify the quality of the automated segmentation. Our segmentation pipeline involves a Fiji plugin which implement active meshes deformation and allows a user to create training data, automatically obtain segmentation meshes from original image data or neural network prediction, and manually curate segmentation data to identify and correct mistakes. Our active meshes-based approach facilitates segmentation postprocessing, correction, and integration with neural network prediction.

Statement of significance

In vitro culture of organ-like structures derived from stem cells, so-called organoids, allows to image tissue morphogenetic processes with high temporal and spatial resolution. Three-dimensional segmentation of cell shape in timelapse movies of these developing organoids is however a significant challenge. In this work, we propose an image analysis pipeline for cell aggregates that combines deep learning with active contour segmentations. This combination offers a flexible and efficient way to segment three-dimensional cell images, which we illustrate with by segmenting datasets of growing mammary gland organoids and mouse embryonic stem cells.
BridgePRS: A powerful trans-ancestry Polygenic Risk Score method
Authors: Hoggart Clive , Choi Shing Wan , García-González Judit , Souaiaia Tade , Preuss Michael , O’Reilly Paul
Published: February 2023

Polygenic Risk Scores (PRS) have huge potential to contribute to biomedical research and to a future of precision medicine, but to date their calculation relies largely on Europeanancestry GWAS data. This global bias makes most PRS substantially less accurate in individuals of non-European ancestry. Here we presentBridgePRS, a novel Bayesian PRS method that leverages shared genetic effects across ancestries to increase the accuracy of PRS in non-European populations. The performance ofBridgePRSis evaluated in simulated data and real UK Biobank (UKB) data across 19 traits in African, South Asian and East Asian ancestry individuals, using both UKB and Biobank Japan GWAS summary statistics.BridgePRSis compared to the leading alternative,PRS-CSx, and two single-ancestry PRS methods adapted for trans-ancestry prediction. PRS trained in the UK Biobank are then validated out-of-cohort in the independent Mount Sinai (New York) BioMeBiobank. Simulations reveal thatBridgePRSperformance, relative toPRS-CSx, increases as uncertainty increases: with lower heritability, higher polygenicity, greater between-population genetic diversity, and when causal variants are not present in the data. Our simulation results are consistent with real data analyses in whichBridgePRShas better predictive accuracy in African ancestry samples, especially in out-of-cohort prediction (into BioMe), which shows a 60% boost in meanR2compared toPRS-CSx(P= 2×10−6).BridgePRSperforms the full PRS analysis pipeline, is computationally efficient, and is a powerful method for deriving PRS in diverse and under-represented ancestry populations.
SICKO: Systematic Imaging ofCaenorhabditisKilling Organisms
Authors: Espejo Luis S. , Freitas Samuel , Hofschneider Vanessa , Chang Leah , Antenor Angelo , Balsa Jonah , Haskins Anne , DeNicola Destiny , Dang Hope , Hamming Sage , Kelser Delaney , Sutphin George L.
Published: February 2023

Caenorhabditis elegansare an important model system for research on host-microbe interaction. Their rapid life cycle, short lifespan, and transparent body structure allow simple quantification of microbial load and the influence of microbial exposure on host survival.C. eleganshost-microbe interaction studies typically examine group survival and infection severity at fixed timepoints. Here we present an imaging pipeline, Systematic Imaging ofCaenorhabditisKilling Organisms (SICKO), that allows longitudinal characterization of microbes colonizing isolatedC. elegans, enabling dynamic tracking of tissue colonization and host survival in the same animals. Using SICKO, we show thatEscherichia coliorPseudomonas aeruginosagut colonization dramatically shortensC. eleganslifespan and that immunodeficient animals lackingpmk-1are more susceptible to colonization but display similar colony growth relative to wild type. SICKO opens new avenues for detailed research into bacterial pathogenesis, the benefits of probiotics, and the role of the microbiome in host health.
Domestic dogs maintain positive clinical, nutritional, and hematological health outcomes when fed a commercial plant-based diet for a year
Authors: Linde Annika , Lahiff Maureen , Krantz Adam , Sharp Nathan , Ng Theros T. , Melgarejo Tonatiuh
Published: February 2023

Objective

Domestic dogs can maintain health on complete and well-balanced canine plant-based nutrition (K9PBN). Novel insight on health outcomes in dogs consuming K9PBN is of relevance to veterinary professionals and consumers given a growing interest in non-traditional dog foods with perceived health benefits, while considering potential safety concerns. We aimed to investigate nutritional equivalence by measuring clinical health outcomes in adult dogs fed K9PBN over twelve months compared to a meat-based diet at baseline.

Animals

Fifteen clinically healthy adult dogs living in households in Los Angeles County, California.

Procedures

Prospective cohort study evaluating clinical, hematological, and nutritional parameters in dogs at 0, 6, and 12 months, including complete blood count (CBC), blood chemistry, cardiac biomarkers, plasma amino acids, and serum vitamin concentrations.

Results

Clinically healthy, client-owned, adult dogs maintain health, based on physical exams, CBC, serum chemistry, plasma amino acids, serum vitamins, and cardiac biomarkers combined with client-reported observations, when fed commercial K9PBN over a twelve-month period.

Clinical Relevance

This study is the most comprehensive and longest known K9PBN investigation to date. It provides clinically important evidence-based nutrition data and new knowledge on outcomes in clinically healthy dogs who maintain health without consumption of animal-derived ingredients. Also, it is of major relevance to One Health paradigms since ingredients produced independent of industrial food animal production are both more sustainable and help to circumvent ethical dilemmas for maintenance of health in domestic dogs.
Characterization of the pearl millet cultivation environments in India: status and perspectives enabled by expanded data analytics and digital tools
Authors: Garin Vincent , Choudhary Sunita , Murugesan Tharanya , Kaliamoorthy Sivasakthi , Diancumba Madina , Hajjarpoor Amir , Satyavathi Tara , Gupta SK , Kholova Jana
Published: February 2023

The cultivation of pearl millet in India is experiencing important transformations due to changes in weather, socio-economic trends, and technological progress. In this scope, we propose a new characterization of the pearl millet production environment in India using the latest available data and methodology. For that, we constructed a database incorporating data on various aspects of pearl millet cultivation at the district level from 1998 to 2017. We complemented this analysis using extensive pearl millet agri-system simulations to evaluate crop models’ abilities to reconstruct and analyse the system at an unprecedented scale. We also proposed a new method to infer system parameters from crop model data. Our results show important differences compared to the characterization currently used. The East part of the pearl millet tract (East Rajasthan, Haryana, Uttar Pradesh, and Madhya Pradesh) emerges as the only region where pearl millet cultivation has grown with potential surplus that is likely exported. Important reductions of pearl millet cultivated area in Gujarat, Maharashtra and Karnataka are potentially due to economy-driven transition to other more pro table crops like cotton, maize, or castor bean. The data used also point toward a constant increase of the rain during the growing season which could have major consequences on the future of this crop, with potential positive effects like extra yield but also negative like extra pressure due to more intense and erratic rainfall or transition to more pro table crops requiring more water. Despite difficulties to predict pearl millet yield in rapidly changing environments, the tested crop models reflected reasonably well the pearl millet production system, thus, setting the base for effective system design in future climatic scenarios. Our data and results have been gathered in an open-source interactive online application.
Molecular control of endurance training adaptation in mouse skeletal muscle
Authors: Furrer Regula , Heim Barbara , Schmid Svenia , Nordström Karl J.V. , Dilbaz Sedat , Ritz Danilo , Adak Volkan , Steurer Stefan A. , Walter Jörn , Handschin Christoph
Published: February 2023

Skeletal muscle has an enormous plastic potential to adapt to various external and internal perturbations. While morphological changes in endurance-trained muscles are well-described, the molecular underpinnings of training adaptation are poorly understood. We aimed at defining the molecular signature of a trained muscle and unraveling the training statusdependent responses to an acute bout of exercise. Our results reveal that even though at baseline, the transcriptomes of trained and untrained muscles are very similar, training status substantially affects the transcriptional response to an acute challenge, both quantitatively and qualitatively, in part mediated by epigenetic modifications. Second, proteomic changes were elicited by different transcriptional modalities. Finally, transiently activated factors such as the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) are indispensable for normal training adaptation. Together, these results provide a molecular framework of the temporal and training status-dependent exercise response that defines muscle plasticity in training.

HIGHLIGHTS

Very few persistent transcriptional events define the trained muscle.

The training status determines the acute exercise response.

Epigenetic changes shape the transcriptional specification of trained muscle.

Absence of the key regulator PGC-1α causes suboptimal training adaptations.
rphenoscate: An R package for semantic-aware evolutionary analyses of anatomical traits
Authors: Porto Diego S. , Tarasov Sergei , Charpentier Caleb , Lapp Hilmar , Balhoff James P. , Vision Todd J. , Dahdul Wasila M. , Mabee Paula M. , Uyeda Josef
Published: February 2023

Organismal anatomy is a complex hierarchical system of interconnected anatomical entities often producing dependencies among multiple morphological characters. Ontologies provide a formalized and computable framework for representing and incorporating prior biological knowledge about anatomical dependencies in models of trait evolution. Further, ontologies offer new opportunities for assembling and working with semantic representations of morphological data.

In this work we present a new R package—rphenoscate—that enables incorporating ontological knowledge in evolutionary analyses and exploring semantic patterns of morphological data. In conjunction withrphenoscapeit also allows for assembling synthetic phylogenetic character matrices from semantic phenotypes of morphological data. We showcase the new package functionalities with three data sets from bees and fishes.

We demonstrate that ontology knowledge can be employed to automatically set up ontologyinformed evolutionary models that account for trait dependencies in the context of stochastic character mapping. We also demonstrate how ontology annotations can be explored to interrogate patterns of morphological evolution. Finally, we demonstrate that synthetic character matrices assembled from semantic phenotypes retain most of the phylogenetic information of the original data set.

Ontologies will become an increasingly important tool not only for enabling prior anatomical knowledge to be integrated into phylogenetic methods but also to make morphological data FAIR compliant—a critical component of the ongoing ‘phenomics’ revolution. Our new package offers key advancements toward this goal.
Multidimensional Characterization of Soft-Tissue Sarcomas with FUS-TFCP2 or EWSR1-TFCP2 Fusions
Authors: Schöpf Julia , Uhrig Sebastian , Heilig Christoph E. , Lee Kwang-Seok , Walther Tatjana , Carazzato Alexander , Dobberkau Anna Maria , Weichenhan Dieter , Plass Christoph , Hartmann Mark , Diwan Gaurav D. , Carrero Zunamys , Ball Claudia R. , Hohl Tobias , Kindler Thomas , Rudolph-Hähnel Patricia , Nilsson Anna , Øra Ingrid , Imle Roland , Banito Ana , Russell Robert B. , Jones Barbara C. , Lipka Daniel B. , Glimm Hanno , Hübschmann Daniel , Hartmann Wolfgang , Fröhling Stefan , Scholl Claudia
Published: February 2023

Linking clinical multi-omics analyses with mechanistic studies provides opportunities to explore the pathogenesis of rare cancers. We leveraged two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective systemic therapies. All tumors exhibited outlier expression of the ALK receptor tyrosine kinase, which was partly accompanied by intragenic deletions and aberrant splicing, resulting in truncated ALK variants that were oncogenic and sensitive to ALK inhibitors. Additional recurrent alterations included CKDN2A/MTAP co-deletions, providing a rationale for therapies targeting CDK4/6 and PRMT5. Functional studies showed that FUS-TFCP2 blocks myogenic differentiation and induces transcription of ALK and a truncated form of TERT through binding outside their regular promoters. Furthermore, FUS-TFCP2 inhibited DNA double-strand break repair. Consistent with this, and unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibited marked genomic instability and signs of defective homologous recombination. DNA methylation profiling indicated a close relationship with undifferentiated sarcomas rather than rhabdomyosarcoma. Finally, we identified patients in whom overt disease was preceded by benign lesions carrying TFCP2 fusions, providing insight into stepwise sarcomagenesis and suggesting new approaches to early detection and interception.

SIGNIFICANCE

Most rare cancers are poorly understood, and pathogenesis-directed therapies are often lacking, resulting in poor patient outcomes. This study illustrates the potential of linking precision oncology programs with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers that could improve the clinical management of such diseases.
Scorpionfish BPI is highly active against multiple drug-resistantPseudomonas aeruginosaisolates from cystic fibrosis patients
Authors: Holzinger Jonas M. , Toelge Martina , Werner Maren , Ederer Katharina U. , Siegmund Heiko , Peterhoff David , Blaas Stefan , Gisch Nicolas , Brochhausen-Delius Christoph , Gessner André , Bülow Sigrid
Published: February 2023

Chronic pulmonary infection is a hallmark of cystic fibrosis (CF) and requires continuous antibiotic treatment. In this context,Pseudomonas aeruginosa(Pa) is of special concern since colonizing strains frequently acquire multiple drug resistance (MDR). Bactericidal/permeability-increasing protein (BPI) is a neutrophil-derived, endogenous protein with high bactericidal potency against Gram-negative bacteria. However, a significant range of CF patients produce anti-neutrophil cytoplasmic antibodies against BPI (BPI-ANCA) thereby neutralizing its bactericidal function. In accordance with literature, we describe that 54.3% of a total of 46 CF patients expressed BPI-ANCA. Importantly, an orthologous protein to human BPI (huBPI) derived from the scorpionfishSebastes schlegelii(scoBPI) completely escaped recognition by these autoantibodies. Moreover, scoBPI exhibited high anti-inflammatory potency towardsPaLPS, and was bactericidal against MDRPaderived from CF patients at nanomolar concentrations. In conclusion, our results highlight the potential of highly active orthologous proteins of huBPI in treatment of MDRPainfections, especially in the presence of BPI-ANCA.
Determination of oligomeric organization of membrane proteins from native membranes at nanoscale-spatial and single-molecule resolution
Authors: Walker Gerard , Brown Caroline , Ge Xiangyu , Kumar Shailesh , Muzumdar Mandar D. , Gupta Kallol , Bhattacharyya Moitrayee
Published: February 2023

The oligomeric organization of membrane proteins in native cell membranes is a critical regulator of their function. High-resolution quantitative measurements of oligomeric assemblies and how they change under different conditions are indispensable to the understanding of membrane protein biology. We report a single-molecule imaging technique (Native-nanoBleach) to determine the oligomeric distribution of membrane proteins directly from native membranes at an effective spatial resolution of ∼10 nm. We achieved this by capturing target membrane proteins in “native nanodiscs” with their proximal native membrane environment using amphipathic copolymers. We established this method using structurally and functionally diverse membrane proteins with well-established stoichiometries. We then applied Native-nanoBleach to quantify the oligomerization status of a receptor tyrosine kinase (TrkA) and a small GTPase (KRas) under conditions of growth-factor binding or oncogenic mutations, respectively. Native-nanoBleach provides a sensitive, single-molecule platform to quantify membrane protein oligomeric distributions in native membranes at an unprecedented spatial resolution.
Atomistic molecular insight on Angiotensin-(1-7) interpeptide interactions
Authors: Chi L. América , Asgharpour Somayeh , Blanco-Rodríguez Rodolfo , Martínez-Archundia Marlet
Published: February 2023

Angiotensin-(1-7) is an endogenous peptide with vaso-protective, anti-oxidant, and anti-inflammatory effects which has been proposed as a potential therapeutic agent in a wide range of clinical conditions. Angiotensin-(1-7) presents a pH-dependent physical instability in aqueous solutions; however, it still lacks a proper atomistic study that provides insights into this behavior and its potential implications. Hence, we studied the formation of early Angiotensin-(1-7) oligomeric aggregates in an aqueous environment under acidic and neutral conditions; physiological and high ionic strength; and high and low peptide concentrations using all-atom Molecular Dynamics simulations. Our main findings are: 1) at acidic pH, there is a poor level of Angiotensin-(1-7) clustering, while, 2) at neutral pH, peptides aggregate in a unique cluster, in good trend with experimental physical instability reports and 3) an increase in salt concentration at acidic pH gives place to aggregation similar to the case at neutral pH. Our results open the route for the modulation of Angiotensin-(1-7) aggregation through a combination of salt concentration and pH conditions. Our protocol (MD + cluster analysis + amino acids interaction map analysis) is general and could be applied to other peptides to study the inter-peptide interaction mechanisms.
Sibling Similarity Can Reveal Key Insights Into Genetic Architecture
Authors: Souaiaia Tade , Wu Hei Man , Hoggart Clive , O'Reilly Paul
Published: February 2023

The use of siblings to infer the factors influencing complex traits has been a cornerstone of quantitative genetics. Here we utilise siblings for a novel application: the identification of genetic architecture, specifically that in individuals with extreme trait values (e.g. in the top 1%). Establishing genetic architecture in these individuals is important because they are at greatest risk of disease and are most likely to harbour rare variants of large effect due to natural selection. We develop a theoretical framework that derives expected trait distributions of siblings based on an index sibling's trait value and trait heritability. This framework is used to develop statistical tests that can infer complex genetic architecture in trait tails, distinguishing between polygenic, de novo and Mendelian tail architecture. We apply our tests to UK Biobank data here, while they can be used to infer genetic architecture in any cohort or health registry that includes siblings, without requiring genetic data. We describe how our approach has the potential to help disentangle the genetic and environmental causes of extreme trait values, to identify individuals likely to carry pathogenic variants for follow-up clinical genetic testing, and to improve the design and power of future sequencing studies to detect rare variants.
Anticipating change: the impact of simulated seasonal heterogeneity on heat tolerances along a latitudinal cline
Authors: Lush Jared , Sgrò Carla M. , Hall Matthew D.
Published: February 2023

An understanding of thermal limits and variation across geographic regions is central to predicting how any population may respond to scenarios of global change. Latitudinal clines, in particular, have been used in demonstrating that populations can be locally adapted to their own thermal environment and, as a result, not all populations will be equally impacted by an increase in temperature. But how robust are these signals of thermal adaptation to the other ecological challenges that animals commonly face in the wild? Seasonal changes in population density, food availability, or photoperiod are common ecological challenges that could disrupt patterns of thermal tolerance along a cline if each population differentially used these signals to anticipate future temperatures and adjust their thermal tolerances accordingly. In this study, we aimed to test the robustness of a cline in thermal tolerance to simulated signals of seasonal heterogeneity. Experimental animals were derived from clones of the Australian water flea,Daphnia carinata, sampled from nine populations along a latitudinal transect in eastern Australia. We then factorially combined summer (18h light, 6h dark) and winter (6h light, 18h dark) photoperiods with high (5 million algal cells individual-1day-1) and low (1 million algal cells individual-1day-1) food availabilities, before performing static heat shock assays and recording knockdown times as a measure of thermal tolerance. In general, higher food availably led to an increase in thermal tolerances, with the magnitude of increase varying by clone. In contrast, summer photoperiods led to rank order changes in thermal tolerances, with heat resistance increasing for some clones, and other decreasing for others. Heat resistance, however, still declined along the latitudinal cline, irrespective of the manipulation of seasonal signals, with northern clones always showing greater thermal resistance, and that this was most likely driven by adaptation to winter thermal conditions. While photoperiod and food availability can clearly shape thermal tolerances for specific clones or populations, they are unlikely to be used to anticipate future temperatures, and thus observed clines in heat resistance will remained robust to these forms of seasonal heterogeneity.