bluuebunny/crossref_metadata_2025 huggingface dataset:
Elimusertib outperforms standard of care chemotherapy in preclinical patient-derived pediatric solid tumor models
Authors: Pusch Fabian , Dorado García Heathcliff , Xu Robin , Gürgen Dennis , Bei Yi , Brueckner Lotte , Röefzaad Claudia , von Stebut Jennifer , Bardinet Victor , Chamorro González Rocío , Eggert Angelika , Schulte Johannes H. , Hundsdörfer Patrick , Seifert Georg , Haase Kerstin , Schaefer Beat , Wachtel Marco , Kühl Anja A. , Ortiz Michael V. , Wengner Antje M. , Scheer Monika , Henssen Anton G.
Published: November 2022

The small molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), elimusertib, is currently being tested clinically in various cancer entities in adults and children. Its preclinical anti-tumor activity in pediatric malignancies, however, is largely unknown. We here assessed the preclinical activity of elimusertib in >40 cell lines and >30 patient-derived xenograft (PDX) models derived from common pediatric solid tumor entities. Detailedin vitroandin vivomolecular characterization of the treated models enabled the evaluation of response biomarkers. Pronounced objective response rates were observed for elimusertib monotherapy in PDX, when treated with a regimen currently used in clinical trials. Strikingly, elimusertib outperformed standard of care chemotherapies, particularly in alveolar rhabdomysarcoma PDX. Thus, elimusertib has strong preclinical anti-tumor activity in pediatric solid tumor models, which may translate to clinically meaningful responses in patients.

Statement of translational relevance

Elimusertib is a small molecule inhibitor of ATR. ATR inhibitors have shown promising results as anticancer agents in adult cancers, but there is limited information on their effectiveness in pediatric solid tumors. Using a cohort of 32 patient-derived xenografts from pediatric solid tumors, we here evaluated the therapeutic potential of elimusertibin vivo. Elimusertib reduced tumor volume growth in all samples. Elimusertib had very limited toxicity and was potent even in tumors with preexisting chemoresistance. Our preclinical data indicates that elimusertib is a safe and potent therapeutic option for pediatric solid tumors. This data may serve as a rationale for the development of pediatric clinical trials for ATR inhibitors.
Genomic innovation and horizontal gene transfer shaped plant colonization and biomass degradation strategies of a globally prevalent fungal pathogen
Authors: Sahu Neha , Indic Boris , Wong-Bajracharya Johanna , Merényi Zsolt , Ke Huei-Mien , Ahrendt Steven , Monk Tori-Lee , Kocsubé Sándor , Drula Elodie , Lipzen Anna , Bálint Balázs , Henrissat Bernard , Andreopoulos Bill , Martin Francis M. , Harder Christoffer Bugge , Rigling Daniel , Ford Kathryn L. , Foster Gary D. , Pangilinan Jasmyn , Papanicolaou Alexie , Barry Kerrie , LaButti Kurt , Virágh Máté , Koriabine Maxim , Yan Mi , Riley Robert , Champramary Simang , Plett Krista L. , Grigoriev Igor V. , Tsai Isheng Jason , Slot Jason , Sipos György , Plett Jonathan , Nagy László G.
Published: November 2022

Members of the fungal genusArmillariaare necrotrophic pathogens with efficient plant biomass-degrading strategies. The genus includes some of the largest terrestrial organisms on Earth, spreading underground and causing tremendous losses in diverse ecosystems. Despite their global importance, the mechanism by whichArmillariaevolved pathogenicity in a clade of dominantly non-pathogenic wood-degraders (Agaricales) remains elusive. Here, using new genomic data, we show thatArmillariaspecies, in addition to widespread gene duplications andde novogene origins, appear to have at least 775 genes that were acquired via 101 horizontal gene transfer (HGT) events, primarily from Ascomycota. Functional and expression data suggest that HGT might have affected plant biomass-degrading and virulence abilities ofArmillaria, two pivotal traits in their lifestyle. We further assayed gene expression during root and cambium colonization, and report putative virulence factors, extensive regulation of horizontally acquired and wood-decay related genes as well as novel pathogenicity-induced small secreted proteins (PiSSPs). Two PiSSPs induced necrosis in live plants, suggesting they are potential virulence effectors conserved acrossArmillaria. Overall, this study details how evolution knitted together horizontally and vertically inherited genes in complex adaptive traits, such as plant biomass degradation and pathogenicity, paving the way for development of infection models for one of the most influential pathogens of temperate forest ecosystems.
An improved network alignment algorithm of dynamic protein interaction networks of floral development inArabidopsis
Authors: Ji Jiamin , Zheng Kailing , He Miao
Published: November 2022

To align the dynamic protein-protein interaction networks (DPINs) might help to better understand the molecular network genetic mechanisms of flower development inArabidopsis thaliana. In this paper, the microarray data of flower development inArabidopsiswere obtained from the gene expression omnibus (GEO) database. The active expressed genes at each time point were screened using σ method. The DPIN at each time point were reconstructed using search tool for the retrieval of interacting genes/proteins (STRING) and then visualized with Cytoscape, and enrichment analysis implemented using clusterProfiler package of the R language. We improved NetCoffee 2, a multi-time, multidimensional, and multi-level network alignment algorithm, NetCoffee 2+, was developed for floral development of A. thaliana. In this paper, a network alignment algorithm applied toA. thaliana, NetCoffee 2+, was developed, and the key proteins and protein complexes during floral development inA. thalianawere mined, with new potential ABCDE-like genes discovered.
ADrosophilaWolfram Syndrome 1 (WFS1) homologue synergises with the intracellular Ca2+release channel, IP3R to affect mitochondrial morphology and function
Authors: Kunnappallil Rose Sebastian , Hasan Gaiti
Published: November 2022

Wolfram syndrome (WFS) is an autosomal recessive neurodegenerative disorder, 90% of which is caused by loss of function of the endoplasmic reticular membrane protein Wolframin or WFS 1. Wolfram syndrome results in Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness (DIDMOAD) in humans. In mammalian cells WFS1 interacts with the ER-localised intracellular Ca2+release channel, Inositol Trisphosphate Receptor 1 (IP3R1) required for IP3mediated Ca2+release from the endoplasmic reticulum.

Here, we tested functional interactions between IP3R and WFS1 mutants in the context of organismal behaviour and neuronal mitochondrial morphology and physiology in a subset of central dopaminergic neurons ofDrosophila melanogaster. We show strong genetic interactions between trans-heterozygotes ofwfs1anditpr(IP3R) mutants by measuring flight deficits. Over-expression of wild-type cDNAs of either interacting partner,wfs1+oritpr+rescued the flight deficits. Cellular studies demonstrate changes in mitochondrial Ca2+entry accompanied by enlarged or swollen mitochondria and decreased mitochondrial content in genotypes that are flight defective. Inwfs1mutant as well aswfs1knockdown conditions a reduction in the number of dopaminergic neurons was observed.

Thus, WFS1 interaction with the IP3R is required in flight regulating central dopaminergic neurons ofDrosophila, for optimal mitochondrial Ca2+entry and maintaining mitochondrial morphology. Our study demonstrates thatDrosophilacan be a good model system to understand the cellular and molecular basis of Wolfram syndrome, its impact on systemic physiology and suggests its use in testing putative pharmaceutical interventions.
Comparative pharmacology of direct oral anticoagulants and vitamin K antagonist
Authors: Kumar Arun HS
Published: November 2022

Background

The prevalence of thrombus and use of anticoagulants is routine in clinical cardiology practice. Vitamin K antagonists (VKA) and/or Direct oral anticoagulants (DOAC) are used for resolution of the thrombus. Despite similar anticoagulation efficacy, use of DOAC is preferred due to their superior safety margin and reduced risk of bleeding. Currently the following DOAC are available for the prevention of thrombosis, i.e., dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban. This study evaluates the comparative pharmacology of these DOAC and VKA to assess clinical preference.

Materials and Methods

The human specific targets of DOAC and VKA (Warfarin) were identified from the SwissTargetPrediction server and analysed for their affinity. The targets were subclassified into functional categories and the relative proportion of each of the functional categories among the total number of targets was estimated. A novel concentration affinity (CA) ratio system was developed for the drugs to assess their safety margin and compared.

Results

The following targets were identified has high affinity targets of DOAC or VKA i.e., coagulation factor X, hERG, matriptase, multidrug and toxin extrusion protein 1, plasminogen, quinone reductase 1 & 2, serine protease hepsin, solute carrier family 22 member 2 and thrombin. Apixaban and rivaroxaban were observed to have superior anticoagulation pharmacology compared to the other DOAC or VKA. Edoxaban and betrixaban were observed to have affinity against hERG, which carries the risk of prolonging QT interval and triggering ventricular tachyarrhythmia.

Conclusion

This study shows the comparative pharmacology of DOAC and VKA and suggests preferential use of apixaban or rivaroxaban due to their superior pharmacodynamic effects and wider safety margin.
Contribution of host species and pathogen clade to snake fungal disease hotspots in Europe
Authors: Blanvillain Gaëlle , Lorch Jeffrey M. , Joudrier Nicolas , Bury Stanislaw , Cuenot Thibault , Franzen Michael , Martínez-Freiría Fernando , Guiller Gaëtan , Halpern Bálint , Kolanek Aleksandra , Kurek Katarzyna , Lourdais Olivier , Michon Alix , Musilová Radka , Schweiger Silke , Szulc Barbara , Ursenbacher Sylvain , Zinenko Oleksandr , Hoyt Joseph R.
Published: November 2022

1. Infectious diseases are influenced by interactions between host and pathogen, and are rarely homogenous across the landscape. Areas with elevated pathogen prevalence maintain a high force of infection, can facilitate pathogen spread to new regions, and may indicate areas with impacts on host populations. However, isolating the ecological processes that result in increases in infection prevalence and intensity remains a challenge.

2. Here we elucidate the contribution of pathogen clade and host species in disease hotspots ofOphidiomyces ophidiicola,the pathogen that causes snake fungal disease, in 21 species of snakes infected with multiple pathogen strains across 10 countries in Europe.

3. We found isolated areas of disease hotspots in a landscape where infections were otherwise low.O. ophidiicolaclade had important effects on transmission, and areas with multiple pathogen clades had higher host infection prevalence. Snake species identity further influenced infection, with most positive detections coming from theNatrixgenus. Most species present in the community only experienced increased levels of infection when multiple strains were present. However, one species,N. tessellata, appeared highly susceptible, having increased infection prevalence regardless of pathogen strain, indicating that this species may be important in pathogen maintenance.

4. Our results suggest that both host and pathogen identity are essential components contributing to increased pathogen prevalence. More broadly, our findings indicate that coevolutionary relationships between hosts and pathogens may be key mechanisms explaining variation in landscape patterns of disease.
The usage of transcriptomics datasets as sources of Real-World Data for clinical trialling
Authors: Matos-Filipe Pedro , García-Illarramendi Juan Manuel , Jorba Guillem , Oliva Baldo , Farrés Judith , Mas José Manuel
Published: November 2022

Background

Randomised Clinical Trials (RCT) reflect results within their specific controlled settings, necessitating further studies to understand outcomes across all possible scenarios. The usage of Real-World Data (RWD) has been recently considered to be a viable alternative to overcome these issues and complement clinical conclusions. Molecular profiles of patients captured by high-throughput measures reflect their medical conditions. When this information is linked to clinical and demographical information, nuances in transcriptomics data can uncover subtle variations in disease pathways among distinct patient groups. This work focuses on the construction of a patient repository database with molecular and clinical information resulting from the integration of publicly available transcriptomics datasets.

Results

Patient data were integrated into the patient repository by using a novel post-processing technique allowing for the usage of samples originating from different/multiple Gene Expression Omnibus (GEO) datasets. Our post-processing technique, which we have named MicroArray Cross-plAtfoRm pOst-prOcessiNg (MACAROON), aims to standardise and integrate transcriptomics data (considering batch effects and possible processing-originated artefacts). This process was able to better reproduce the down streaming biological conclusions in a 45% improvement compared to other methods available. Furthermore, RWD was mined from GEO samples’ metadata and a clinical and demographical characterisation of the database was obtained. RWD mining was done through a manually curated synonym dictionary allowing for the correct assignment (95.33% median accuracy; 80.14% average) of medical conditions.

Conclusions

Our strategy produced a repository, which includes molecular, clinical and demographical RWD by integrating multiple public datasets. The exploration of these data facilitates the discovery of clinical outcomes and molecular pathways specific to predetermined patient populations.
SETD2 Deficiency Promotes Inflammatory Bowel Disease via Oxidative Stress and FasL-induced Apoptosis
Authors: Wang Yueduo , Shen Shenghai , Li Li
Published: November 2022

SET-domain-containing 2 (SETD2) is known as the major trimethyltransferase that regulates the methylation of histone H3 lysine 36 (H3K36), which has been found frequently mutated in IBD samples. Although SETD2 deficiency has been proven to modulate oxidative stress, the specific mechanisms of SETD2 in IBD are still little known. To investigate the possible role of SETD2 in IBD, we generated and genotyped epithelium-specific deletion ofSetd2(Setd2Vil-KO) progeny mice to establish mice IBD pathology model and then studied molecular expression differences at mRNA and protein levels in the intestinal epithelial tissue ofSetd2Vil-KOmice. Compared withSetd2F/Fmice, the tissue ofSetd2Vil-KOmice showed increases in oxidative stress and cell apoptosis level via RT-qPCR, while TUNEL assay and immunofluorescence showed significantly enhanced apoptotic signaling and FasL expression. Together, our findings highlight that SETD2 regulates oxidative stress and FasL-induced apoptosis inSetd2Vil-KOmice intestinal epithelial cells through epigenetics mechanisms, which plays an essential role in IBD pathogenesis. Therefore, our study provides new insights into the prevention and therapy of IBD from the perspective of epigenetic regulation.
Latch Verified Bulk-RNA Seq toolkit: a cloud-based suite of workflows for bulk RNA-seq quality control, analysis, and functional enrichment
Authors: Le Hannah G.B.H. , Steenwyk Jacob L. , Manske Nathan , Smolin Max , Abdulali Aidan , Kamat Ayush , Kanchana Rohan , Giffin Kyle , Andere Alfredo , Workman Kenny
Published: November 2022

Background

Analysis of high-throughput bulk RNA-sequencing (RNA-seq) data reveals changes in gene expression between diverse conditions. Many tools have emerged to quality control RNA-seq reads, quantify expression levels, conduct functional enrichment among differentially expressed genes, or identify differential RNA splicing. However, unified toolkits for conducting these analyses are lacking. Moreover, existing software does not use cloud-based platforms that provide the necessary storage and computational resources to process RNA-seq data or intuitive graphical interfaces for easy use by experimental and computational scientists.

Results

To address these challenges, we introduce the Latch Verified Bulk RNA-Seq (LVBRS) toolkit, a flexible suite of programs packaged into a single workflow coupled with a graphical user interface for conducting quality control, transcript quantification, differential splicing, differential expression analysis, and functional enrichment analyses. For functional enrichment, the LVBRS toolkit supports three databases—Gene Ontology, KEGG Pathway, and Molecular Signatures database—capturing diverse functional information. We demonstrate the utility of the LVBRS toolkit by reanalyzing a publicly available dataset examining the impact of severe and mild models of hypoxia—induced by Cobalt (II) Chloride (CoCl2) and oxyquinoline treatment, respectively—on a human colon adenocarcinoma cell line. Our analyses reveal CoCl2treatment results in more differentially expressed genes, recapitulating previously reported results that CoCl2models more severe hypoxia. Moreover, including alternative splicing and functional enrichment analysis using a greater breadth of functional databases revealed additional biological insights—such as greater alternative splicing in the CoCl2condition and differentially expressed DNA repair pathways. These results demonstrate the LVBRS toolkit’s efficacy in facilitating biological insights from bulk RNA-seq data.

Conclusions

The LVBRS toolkit offers a robust unified framework for processing and analyzing Bulk RNA-Seq experiments. The easy-to-use graphical user interface will enable diverse scientists to conduct high-throughput bulk RNA-Seq analysis efficiently. Our aim is that the LVBRS toolkit will help streamline bulk RNA-seq workflows and facilitate deriving biologically meaningful insights from bulk RNA-seq data. The source code is freely available under the MIT license and hosted on the LatchBio Console (https://console.latch.bio/se/bulk-rnaseq), complete with documentation (https://latch.wiki/bulk-rna-seq-end-to-end).
STREAK: A Supervised Cell Surface Receptor Abundance Estimation Strategy for Single Cell RNA-Sequencing Data using Feature Selection and Thresholded Gene Set Scoring
Authors: Javaid Azka , Frost H. Robert
Published: November 2022

The accurate estimation of cell surface receptor abundance for single cell transcriptomics data is important for the tasks of cell type and phenotype categorization and cell-cell interaction quantification. We previously developed an unsupervised receptor abundance estimation technique named SPECK (Surface Protein abundance Estimation using CKmeans-based clustered thresholding) to address the challenges associated with accurate abundance estimation. In that paper, we concluded that SPECK results in improved concordance with Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) data relative to comparative unsupervised abundance estimation techniques using only single-cell RNA-sequencing (scRNA-seq) data. In this paper, we outline a new supervised receptor abundance estimation method called STREAK (gene Set Testing-based Receptor abundance Estimation using Adjusted distances and cKmeans thresholding) that leverages associations learned from joint scRNA-seq/CITE-seq training data and a thresholded gene set scoring mechanism to estimate receptor abundance for scRNA-seq target data. We evaluate STREAK relative to both unsupervised and supervised receptor abundance estimation techniques using two evaluation approaches on three joint scRNA-seq/CITE-seq datasets that represent two human tissue types. We conclude that STREAK outperforms other abundance estimation strategies and provides a more biologically interpretable and transparent statistical model.
The structure of Lepidoptera-plant interaction networks across clades, life stages, and environmental gradients
Authors: Ho Hsi-Cheng , Altermatt Florian
Published: November 2022

Aim

Integrate biogeographic and ecological knowledge to understand the spatial-structural patterns of plant-insect interaction networks at the landscape scale.

Location

The 36,000 km2German state of Baden-Württemberg, Central Europe.

Methods

We integrated extensive data of Lepidoptera-plant occurrences and interactions to inferentially construct local interaction networks across Baden-Württemberg, considering in total 3148 plant and 980 Lepidoptera species, covering butterflies, Noctuid moths, Geometrid moths and Bombycoid moths. We quantified clade- and life-stage-specific network structures and related these features to GIS-informed environmental conditions, thereby revealing the spatial (environmental) patterns and potential drivers of networks’ structural variation across the landscape.

Results

Spanning the same environmental gradients, Lepidoptera clades and life stages can form various interaction structures with food plants and exhibit distinct spatial-structural patterns. For all major Lepidopteran groups, except Geometrid moths, potential diet across life stages tended to broaden toward low-elevation farmlands. The larval and adult networks of butterflies became less modular with farmland coverage; the same for adult Noctuid moths, but the inverse for adult Geometrid moths. With increasing elevation, the larval and adult networks of Noctuid moths became less and more modular, respectively, whereas Geometrid adult networks became more modular. While the adult dietary niche of butterflies was more overlapped at low elevation, those of Noctuid and Geometrid moths further associated with land cover and were more overlapped toward low- and high-elevation farmlands, respectively.

Main conclusions

Environmental factors and biotic interactions together shape ecological communities. By particularly accounting for species-interaction contexts, we revealed the spatial-structural patterns of Lepidoptera-plant networks along geo-climate and land-cover gradients, where the shaping mechanisms likely include both evolutionary (e.g., resource-consumer co-evolution) and ecological (e.g., competitive exclusion) processes and are specific to Lepidoptera’s clade or life stage. Such biogeographical structural patterns provide ecological and conservation implications at both species and community levels, and can indicate the potential response of Lepidoptera-plant communities to environmental changes.
Bladder-draining lymph nodes support germinal centre B cell responses during urinary tract infection in mice
Authors: Hawas Sophia , Vagenas Dimitrios , Haque Ashraful , Totsika Makrina
Published: November 2022

Bacterial urinary tract infections (UTIs) are both common and exhibit high recurrence rates in women. UTI healthcare costs are increasing due to the rise of multi-drug resistant (MDR) bacteria, necessitating alternative approaches for infection control. Here, we investigated whether host adaptive immune responses can influence infection outcomes. We employed a mouse model in which wild-type C57BL/6J mice were transurethrally inoculated with an MDR UTI strain of uropathogenicEscherichia coli(UPEC). Firstly, we noted thatrag1-/-C57BL/6J mice harboured larger bacterial burdens than wild-type counterparts, consistent with a role for T and/or B cells in optimal control of UTI. Consistent with this, UTI triggered in the bladders of wild-type mice early increases of myeloid cells, including CD11chiconventional dendritic cells, suggesting possible involvement of these professional antigen-presenting cells. Importantly, germinal centre (GC) B cell responses developed by 4 weeks post-infection in bladder-draining lymph nodes of wild-type mice, and although modest in magnitude and transient in nature, could not be boosted with a second UTI. Thus, our data reveal for the first time in a mouse model, that Gram-negative bacterial UTI induces local B cell immune responses in bladder-draining lymph nodes, which could potentially serve to control infection.
Estimating the Incidence of Familial Exudative Vitreoretinopathy (FEVR) in The State of Michigan
Authors: Trese Matthew G.J. , Qu Xianggui , Drenser Kimberly A.
Published: November 2022

Background and Objective

Amongst ophthalmologists, familial exudative vitreoretinopathy (FEVR) is agreed to be a rare disease. However, its incidence is currently unknown. The goal of this study is to identify the incidence of FEVR in Michigan.

Study Design/Materials and Methods

This retrospective chart review evaluated new patient encounters from the largest retinal specialty practice within the State of Michigan from over a 6 year period. These identified encounters were queried for the international classification of disease 10 (ICD-10) code (H35.023): exudative retinopathy, not diabetes. Review of both the individual patient encounters and the appropriate clinical imaging resulted in the identification of our FEVR cohort which was subsequently compared with the live birthrate in the State of Michigan over the same 6 years to determine an incidence rate.

Results

This study revealed 44 new FEVR diagnosis and 666, 102 livebirths over the 6 year period of interest. Thus, the incidence of FEVR in the state of Michigan was estimated to be 0.007%. (95% CI[0.005%- 0.009%)

Conclusion

Familial Exudative Vitreoretinopathy is indeed a rare diagnosis with an incidence rate of 0.007% within the State of Michigan.
Transparency in infectious disease research: a meta-research survey of specialty journals
Authors: Zavalis Emmanuel A. , Contopoulos-Ioannidis Despina G. , Ioannidis John P.A.
Published: November 2022

Introduction

Infectious diseases carry a large global burden and have implications for society at large. Therefore, reproducible, transparent research is extremely important. To assess the current state of transparency in this field, we investigated code sharing, data sharing, protocol registration, conflict of interest and funding disclosures in articles published in the most influential infectious disease journals.

Methods

We evaluated transparency indicators in the 5340 PubMed Central Open Access (PMC OA) articles published in 2019 or 2021 in the 9 most-cited specialty journals in infectious disease. We used a previously validated text-mining R package,rtransparent. The approach was manually validated for a random sample of 200 articles for which study characteristics were also extracted in detail. Main comparisons assessed 2019 versus 2021 articles, 2019 versus 2021 non-COVID-19 articles, and 2021 non-COVID-19 articles versus 2021 COVID-19 articles.

Results

A total of 5340 articles were evaluated (1860 published in 2019 and 3480 in 2021 (of which 1828 on COVID-19)). Text-mining identified code sharing in 98 (2%) articles, data sharing in 498 (9%), registration in 446 (8%), conflict of interest disclosures in 4209 (79%) and funding disclosures in 4866 (91%). There were substantial differences across the 9 journals in the proportion of articles fulfilling each transparency indicator: 1-9% for code sharing, 5-25% for data sharing, 1-31% for registration, 7-100% for conflicts of interest, and 65-100% for funding disclosures. There were no major differences between articles published in 2019 and non-COVID-19 articles in 2021. In 2021, non-COVID-19 articles had more data sharing (12%) than COVID-19 articles (4%). Validation-corrected imputed estimates were 3% for code sharing, 11% for data sharing, 8% for registrations, 79% for conflict of interest disclosures and 92% for funding disclosures.

Conclusion

Data sharing, code sharing, and registration are very uncommon in infectious disease specialty journals. Increased transparency is required.
Integrative analysis of GWAS and co-localisation data suggests novel genes associated with age-related multimorbidity
Authors: West Clare E. , Karim Mohd , Falaguera Maria J. , Speidel Leo , Green Charlotte J. , Logie Lisa , Schwartzentruber Jeremy , Ochoa David , Lord Janet M. , Ferguson Michael A. J. , Bountra Chas , Wilkinson Graeme F. , Vaughan Beverley , Leach Andrew R. , Dunham Ian , Marsden Brian D.
Published: November 2022

Advancing age is the greatest risk factor for developing multiple age-related diseases. When developing therapeutics, using a Geroscience approach to target the shared underlying pathways of ageing, rather than individual diseases, may be an effective way to treat and prevent age-related morbidity while potentially reducing the burden of polypharmacy. We harness the Open Targets Platform and Open Targets Genetics Portal to perform a systematic analysis of nearly 1,400 genome-wide association studies (GWAS) mapped to 34 age-related diseases and traits to identify genetic signals that appear to be shared between two or more of these traits. We identify 995 targets with shared genetic links to these age-related diseases and traits, which are enriched in mechanisms of ageing and include known ageing and longevity-related genes. Of these 995 genes, 128 are the target of an approved or investigational drug, 526 have experimental evidence of binding pockets or are predicted to be tractable by small molecule or antibody modality approaches, and 341 have no existing tractability evidence, representing underexplored genes which may reveal novel biological insights and therapeutic opportunities. We present these candidate targets in a web application, TargetAge, to enable the exploration and prioritisation of possible novel drug targets for age-related multimorbidity.
Interferometric nanoparticle tracking analysis enables label-free discrimination of extracellular vesicles from large lipoproteins
Authors: Kashkanova Anna D. , Blessing Martin , Reischke Marie , Baur Andreas S. , Sandoghdar Vahid , Van Deun Jan
Published: November 2022

Extracellular vesicles (EVs) are increasingly gaining interest as biomarkers and therapeutics. Accurate sizing and quantification of EVs remain problematic, given their nanometer size range and small scattering cross-sections. This is compounded by the fact that common EV isolation methods result in co-isolation of particles with comparable features. Especially in blood plasma, similarly-sized lipoproteins outnumber EVs to a great extent. Recently, interferometric nanoparticle tracking analysis (iNTA) was introduced as a particle analysis method that enables determining the size and refractive index of nanoparticles with high sensitivity and precision. In this work, we apply iNTA to differentiate between EVs and lipoproteins, and compare its performance to conventional nanoparticle tracking analysis (NTA). We show that iNTA can accurately quantify EVs in artificial EV-lipoprotein mixtures and in plasma-derived EV samples of varying complexity. Conventional NTA could not report on EV numbers, as it was not able to distinguish between EVs and lipoproteins. iNTA has the potential to become a new standard for label-free EV characterization in suspension.
A Junction-Dependent Mechanism Drives Mammary Cell Intercalation for Ductal Elongation
Authors: Pfannenstein Alexander , Macara Ian G.
Published: November 2022

Mammary glands contain branched networks of ducts and alveoli that function to produce milk for offspring. While the murine luminal epithelium is organized as a cellular monolayer, it originates from multilayered structures called terminal end buds (TEB). The TEBs generate ducts of monolayered epithelial cells as they invade the fat pad, but little is known about underlying mechanisms. While apoptosis provides a plausible mechanism for cavitation of the ductal lumen, it does not account for elongation of ducts behind the TEBs. Our spatial calculations suggest that most cells in TEBs need to intercalate into the outermost luminal layer and that this migration of cells is the primary driver of cavitation and ductal elongation. To study the progression of multilayered to monolayered epithelium, we developed a quantitative cell culture assay that determines the efficiency of intercalation into an epithelial monolayer. Using this tool, we verified that loss of adherens junctions prevents stable integration of cells into monolayers, consistent with previous data in cultured cells and in primary tissue. Interestingly, tight junction (TJ) proteins also play a key role in this integration process. Although loss of the ZO-1 TJ protein in intercalating cells suppresses intercalation, loss of ZO-1 in the monolayer has the reverse effect, promoting intercalation – even though ZO-1 is not necessary for establishment of TJs. ZO-1-positive puncta form between cells and the monolayer, which then resolves into a new intercellular boundary as intercalation proceeds. ZO-1 loss also reduces engraftment when cells are transplanted into the mammary gland via intraductal injection. We further show that intercalation is dependent on dynamic cytoskeletal rearrangements in both the existing monolayer and intercalating cells. These data identify luminal cell rearrangements necessary for mammary gland development and suggest a molecular mechanism for integration of cells into an existing monolayer.
DeepCCI: a deep learning framework for identifying cell-cell interactions from single-cell RNA sequencing data
Authors: Yang Wenyi , Xu Zhaochun , Luo Meng , Cai Yideng , Xu Chang , Wang Pingping , Wei Songren , Xue Guangfu , Jin Xiyun , Cheng Rui , Que Jinhao , Zhou Wenyang , Pang Fenglan , Nie Huan , Jiang Qinghua
Published: November 2022

With the rapid development of high throughput single-cell RNA sequencing (scRNA-seq) technologies, it is of high importance to identify Cell-cell interactions (CCIs) from the ever-increasing scRNA-seq data. However, limited by the algorithmic constraints, current computational methods based on statistical strategies ignore some key latent information contained in scRNA-seq data with high sparsity and heterogeneity. To address the issue, here, we developed a deep learning framework named DeepCCI to identify meaningful CCIs from scRNA-seq data. Applications of DeepCCI to a wide range of publicly available datasets from diverse technologies and platforms demonstrate its ability to predict significant CCIs accurately and effectively.
A DNA origami fiducial for accurate 3D AFM imaging
Authors: Kolbeck Pauline J. , Dass Mihir , Martynenko Irina V. , van Dijk-Moes Relinde J.A. , Brouwer Kelly J.H. , van Blaaderen Alfons , Vanderlinden Willem , Liedl Tim , Lipfert Jan
Published: November 2022

Atomic force microscopy (AFM) is a powerful technique for imaging molecules, macromolecular complexes, and nanoparticles with nanometer-resolution. However, AFM images are distorted by the shape of the tip used. These distortions can be corrected if the tip shape can be determined by scanning a sample with features sharper than the tip and higher than the object of interest. Here we present a 3D DNA origami structure as fiducial for tip reconstruction and image correction. Our fiducial is stable under a broad range of conditions and has sharp steps at different heights that enable reliable tip reconstruction from as few as ten fiducials. The DNA origami is readily co-deposited with biological and non-biological samples, achieves higher precision for the tip apex than polycrystalline samples, and dramatically improves the accuracy of the lateral dimensions determined from the images. Our fiducial thus enables accurate and precise AFM imaging for a broad range of applications.
Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration
Authors: Ng Benjamin , Huang Kevin Y. , Pua Chee Jian , Lim Wei-Wen , Kuthubudeen Fathima , Hii An An , Viswanathan Sivakumar , Petretto Enrico , Cook Stuart A.
Published: November 2022

Following lung injury, alveolar regeneration is characterized by the transformation of alveolar type 2 (AT2) cells, via a transitional KRT8+ state, into alveolar type 1 (AT1) cells. In lung disease, dysfunctional intermediate cells accumulate, AT1 cells are diminished and fibrosis occurs. Using single cell RNA sequencing datasets of human interstitial lung disease, we found that interleukin-11 (IL11) is specifically expressed in aberrant KRT8 expressing KRT5-/KRT17+ and basaloid cells. Stimulation of AT2 cells with IL11 or TGFβ1 caused EMT, induced KRT8+ and stalled AT1 differentiation, with TGFβ1 effects being IL11 dependent. In bleomycin injured mouse lung, IL11 was increased in AT2-derived KRT8+ cells and deletion ofIl11ra1in lineage labeled AT2 cells reduced KRT8+ expression, enhanced AT1 differentiation and promoted alveolar regeneration, which was replicated in therapeutic studies using anti-IL11. These data show that IL11 maintains AT2 cells in a dysfunctional transitional state, impairs AT1 differentiation and blocks alveolar regeneration across species.

Teaser

Interleukin-11 stalls type 2-to-type 1 alveolar epithelial cell differentiation and prevents lung regeneration
A Deep Denoising Sound Coding Strategy for Cochlear Implants
Authors: Gajecki Tom , Zhang Yichi , Nogueira Waldo
Published: November 2022

Cochlear implants (CIs) have proven to be successful at restoring the sensation of hearing in people who suffer from profound sensorineural hearing loss. CI users generally achieve good speech understanding in quiet acoustic conditions. However, their ability to understand speech degrades drastically when background interfering noise is present. To address this problem, current CI systems are delivered with front-end speech enhancement modules that can aid the listener in noisy environments. However, these only perform well under certain noisy conditions, leaving quite some room for improvement in more challenging circumstances. In this work, we propose replacing the CI sound coding strategy with a deep neural network (DNN) that performs end-to-end speech denoising by taking the raw audio as input and providing a denoised electrodogram, i.e., the electrical stimulation patterns applied to the electrodes across time. We specifically introduce a DNN that emulates a common CI sound coding strategy, the advanced combination encoder (ACE). We refer to the proposed algorithm as ‘Deep ACE’. Deep ACE is designed not only to accurately code the acoustic signals in the same way that ACE would but also to automatically remove unwanted interfering noises, without sacrificing processing latency. The model was optimized using a CI-specific loss function and evaluated using objective measures as well as listening tests in CI participants. Results show that, based on objective measures, the proposed model achieved higher scores when compared to the baseline algorithms. Also, the proposed deep learning-based sound coding strategy gave eight CI users the highest speech intelligibility results.
Plastid DNA sequences and oospore characters of some European species ofTolypellasectionTolypella(Obtusifolia, Characeae) indicate a new crypticTolypellaspecies from the Mediterranean island Sardinia
Authors: Holzhausen Anja , Nowak Petra , Ballot Andreas , Becker Ralf , Gebert Jasmina , Gregor Thomas , Karol Kenneth G. , Lambert Elisabeth , Pérez William , Raabe Uwe , Schneider Susanne C. , Stewart Nick , van de Weyer Klaus , Wilde Volker , Schubert Hendrik
Published: November 2022

In Europe, the genusTolypella(Characeae) comprises four to eightTolypellaspecies in sectionsRothiaandTolypellathat have been distinguished by vegetative morphology and gametangial characters such as antheridial size and oospore cell wall ornamentation. However, morphological species differentiation is difficult in some cases due to overlapping and variable vegetative features, which in many cases are difficult to observe clearly.

To clarify the taxonomic status of the five European species ofTolypellain sectionTolypella, sequence data of the plastid genesatpB,rbcL andpsbC forTolypella glomerata(Desv.) Leonh.,Tolypella hispanicaAllen,Tolypella nidifica(O.F. Müll.) A. Braun,Tolypella normaniana(Nordst.) Nordst. andTolypella salinaCor. were combined with data on oospore morphology, including oospore wall ornamentation.

Gene sequence data identified five distinct clusters, but they differed from the morphologically identified five species. ‘T. glomerata’ consisted of some of the samples morphologically identified asT. glomerataand seven samples ofT. normaniana, while the remainingT. glomeratasamples clustered with specimens of unclear affiliation (“Tolypella. sp.”). ‘T. hispanicaI’ consisted of samples from various locations, whereas “T.hispanicaII” consisted of samples ofT. hispanicafrom the Mediterranean island, Sardinia. The remaining cluster consisted of all the specimens that had been determined asT. salinaorT. nidificain addition to two specimens ofT. normaniana. Oospore morphology was most clearly distinguishable forT. glomerata. Oospore characteristics for all other taxa were not as informative but showed some geographical and/or environmentally influenced differences, especially forT. nidificaandT. salina.

Our results suggest a significantly different taxonomy ofTolypellasect.Tolypellain which specimens normally identified asT. glomeratamight be two different species,T. glomerataand an unidentified species;T. nidificaandT. salinaare not separate species;T. normanianais a diminutive variant ofT. nidificaorT. salina; andT. hispanicacomprises two different species, one from the Mediterranean island Sardnia.
Mapping phosphorylation post-translational modifications along single peptides with nanopores
Authors: Nova Ian C. , Ritmejeris Justas , Brinkerhoff Henry , Koenig Theo J. R. , Gundlach Jens H. , Dekker Cees
Published: November 2022

Current methods to detect post-translational modifications (PTMs) of proteins, such as phosphate groups, cannot measure single molecules and often cannot differentiate between closely spaced phosphorylation sites. Using a nanopore sequencing approach, we here report detection of PTMs at the single-molecule level on immunopeptide sequences with cancer-associated phosphate variants. We reliably discriminate peptide sequences with one or two closely spaced phosphates with 95% accuracy for individual reads of single molecules.
Risk Assessment of the newly emerged H7N9 avian influenza viruses
Authors: Chang Pengxiang , Sadeyen Jean-Remy , Bhat Sushant , Daines Rebecca , Hussain Altaf , Yilmaz Huseyin , Iqbal Munir
Published: November 2022

Since the first human case in 2013, H7N9 avian influenza viruses (AIVs) have caused more than 1500 human infections with a mortality rate of approximately 40%. Despite large-scale poultry vaccination regimes across China, the H7N9 AIVs continue to persist and evolve rapidly in poultry. Recently, several strains of H7N9 AIVs have been isolated and shown the ability to escape vaccine-induced immunity. To assess the zoonotic risk of the recent H7N9 AIV isolates, we rescued viruses with hemagglutinin (HA) and neuraminidase (NA) from these H7N9 AIVs and six internal segments from PR8 virus (A/Puerto Rico/8/34 [H1N1]) and characterized their receptor binding, pH of fusion, thermal stability, plaque morphology and in ovo virus replication. We also assessed the cross-reactivity of the viruses with human monoclonal antibodies (mAbs) against H7N9 HA and ferret antisera against H7N9 AIV candidate vaccines. The H7N9 AIVs from the early epidemic waves had dual sialic acid receptor binding characteristics, whereas the more recent H7N9 AIVs completely lost or retained only weak human sialic acid receptor binding. Compared with the H7N9 AIVs from early epidemic waves (2013-2016), the recent (2020/21) viruses formed larger plaques and increased replication titres in ovo, demonstrating increased acid stability but reduced thermal stability. Further analysis showed that these recent H7N9 AIVs had poor cross-reactivity with the human mAbs and ferret antisera, highlighting the need to update the vaccine candidates. To conclude, the newly emerged H7N9 AIVs showed characteristics of typical AIVs, posing reduced zoonotic risk but a heightened threat for poultry.
Targeting of plasmodesmal proteins requires unconventional signals
Authors: Robles Luna Gabriel , Li Jiefu , Wang Xu , Liao Li , Lee Jung-Youn
Published: November 2022

Cellular signaling relies on precise spatial localization and dynamic interactions of proteins within the subcellular compartment or niches, including cell-cell contact sites and connections. In plants, both endogenous and pathogenic proteins gained the ability to target plasmodesmata, the membrane-lined cytoplasmic connections, to regulate or exploit cellular signaling across cell wall boundaries. Those include the receptor-like membrane protein PDLP5, a potent regulator of plasmodesmal permeability that generates feed-forward or -back signals vital for plant immunity and root development. However, little is known about what molecular features determine the plasmodesmal association of PDLP5 or other proteins. Notably, although these proteins each have the ability to target plasmodesmata, no protein motifs or sequences have been identified indicative of targeting signals. To address this knowledge gap, we combined machine learning and targeted mutagenesis approaches. Here we report that PDLP5 and its closely related proteins carry novel targeting signals comprising short stretches of amino acid residues. As for PDLP5, it contains two non-redundant, tandemly arranged signals, either of which is sufficient for both localization and biological function regulating viral movement. Strikingly, plasmodesmal targeting signals exhibit little conservation in sequence but are located similarly proximal to the membrane. These novel unconventional features appear to be a common theme in plasmodesmal targeting.
Two pup vocalization types are genetically and functionally separable in deer mice
Authors: Jourjine N. , Woolfolk M.L. , Sanguinetti-Scheck J.I. , Sabatini J.E. , McFadden S. , Lindholm A.K. , Hoekstra H.E.
Published: November 2022

Vocalization is a widespread vertebrate social behavior that is essential for fitness in the wild. While many vocal behaviors are highly conserved, heritable features of specific vocalization types can vary both within and between species, raising the questions of why and how some vocal behaviors evolve. Here, using new computational tools to automatically detect and cluster vocalizations into distinct acoustic categories, we compare pup isolation calls across neonatal development in eight taxa of deer mice (genusPeromyscus) and compare them to laboratory mice (C57Bl6/j strain) and free-living, wild house mice (Mus musculus musculus). Whereas bothPeromyscusandMuspups produce ultrasonic vocalizations (USVs),Peromyscuspups also produce a second call type with acoustic features, temporal rhythms, and developmental trajectories that are distinct from those of USVs. In deer mice, these tonal and low frequency “cries” are predominantly emitted in postnatal days one through nine, while USVs are primarily made after day nine. Using playback assays, we show that cries result in a more rapid approach byPeromyscusmothers than USVs, suggesting a role for cries in eliciting parental care early in neonatal development. Using genetic crosses between two sister species of deer mice exhibiting large, innate differences in the acoustic structure of cries and USVs, we find that variation in vocalization rate, duration, and pitch display different degrees of genetic dominance and that cry and USV features can be uncoupled in second-generation hybrids. Taken together, this work shows that vocal behavior can evolve quickly between closely related rodent species in which vocalization types, likely serving distinct functions in communication, are controlled by distinct genetic loci.