bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene regulatory network inference from single-cell data using optimal transport
Authors: Lamoline François , Haasler Isabel , Karlsson Johan , Gonçalves Jorge , Aalto Atte
Published: May 2024

Modelling gene expression is a central problem in systems biology. Single-cell technologies have revolutionised the field by enabling sequencing at the resolution of individual cells. This results in a much richer data compared to what is obtained by bulk technologies, offering new possibilities and challenges for gene regulatory network inference. Here we introduce GRIT — a method to fit a differential equation model and to infer gene regulatory networks from single-cell data using the theory of optimal transport. The idea consists in tracking the evolution of the cell distribution over time and finding the system that minimises the transport cost between consecutive time points.
INSIHGT: An accessible multi-scale, multi-modal 3D spatial biology platform
Authors: Yau Chun Ngo , Hung Jacky Tin Shing , Campbell Robert A. A. , Wong Thomas Chun Yip , Huang Bei , Wong Ben Tin Yan , Chow Nick King Ngai , Zhang Lichun , Tsoi Eldric Pui Lam , Tan Yuqi , Li Joshua Jing Xi , Wing Yun Kwok , Lai Hei Ming
Published: May 2024

Biological systems are complex, encompassing intertwined spatial, molecular and functional features. However, methodological constraints always limit the completeness of information that can be extracted. Here, we report the development of INSIHGT, a minimally perturbative, accessible and cost-efficient three-dimensional (3D) spatial biology method utilizing superchaotropes and host-guest chemistry. This allows highly multiplexed and multi-modal readout of tissue biomolecules in biological systems up to centimeter scales, permitting radio-histological correlation of phosphorylated alpha-synuclein pathologies in human hemi-brainstem. The homogeneous penetration permits reliable semi-quantitative signals in 3D compared to reference signals. Diverse antigens, mRNA transcripts, neurotransmitters, and post-translational and epigenetic modifications, are well-preserved and visualized. INSIHGT also allows multi-round molecular probing for high-dimensional spatial biology and compatibility with downstream traditional histology. With INSIHGT, we mapped previously undescribed podocyte-to-parietal epithelial cell microfilaments and demonstrated their geodesic clustering in mouse glomeruli, and catalogued sparsely located neurofilament-intensive inclusion bodies in the human cerebellum, and identified NPY-proximal cell types defined by spatial morpho-proteomics in mouse hypothalamus. We anticipate INSIHGT can form the foundations for 3D spatial multi-omics technology development and holistic systems biology studies.
Invasion and spread of the neotropical leafhopperCurtara insularis(Hemiptera: Cicadellidae) in Africa and North America and the role of high-altitude windborne migration in invasive insects
Authors: Nartey Rita , Chamorro Lourdes , Buffington Matt , Afrane Yaw A. , Mohammed Abdul R. , Owusu-Asenso Christopher M. , Akosah-Brempong Gabriel , Pambit Zong Cosmos Manwovor-Anbon , Hendrix Solomon V. , Dao Adama , Yaro Alpha S. , Diallo Moussa , Sanogo Zana L. , Djibril Samake , Halbert Susan E. , Bamou Roland , Nance Catherine E. , Bartlett Charles R. , Reynolds Don R. , Chapman Jason W. , Obiri-Danso Kwasi , Lehmann Tovi
Published: May 2024

Invasive insects threaten ecosystem stability, public health, and food security. Documenting newly invasive species and understanding how they reach into new territories, establish populations, and interact with other species remain vitally important. Here, we report on the invasion of the South American leafhopper,Curtara insularisinto Africa, where it has established populations in Ghana, encroaching inland at least 350 km off the coast. Importantly, 80% of the specimens collected were intercepted between 160 and 190 m above ground. Further, the fraction of this species among all insects collected was also higher at altitude, demonstrating its propensity to engage in high-altitude windborne dispersal. Its aerial densities at altitude translate into millions of migrants/km over a year, representing massive propagule pressure. Given the predominant south-westerly winds, these sightings suggest an introduction ofC. insularisinto at least one of the Gulf of Guinea ports. To assess the contribution of windborne dispersal to its spread in a new territory, we examine records ofC. insularisrange-expansion in the USA. Reported first in 2004 from central Florida, it reached north Florida (Panhandle) by 2008-2011 and subsequently spread across the southeastern and south-central US. Its expansion fits a “diffusion-like” process with 200—300 km long “annual displacement steps”—a pattern consistent with autonomous dispersal rather than vehicular transport. Most “steps” are consistent with common wind trajectories from the nearest documented population, assuming 2—8 hours of wind-assisted flight at altitude.Curtara insularishas been intercepted at US ports and on trucks. Thus, it uses multiple dispersal modalities, yet its rapid overland spread is better explained by its massive propagule pressure linked with its high-altitude windborne dispersal. We propose that high-altitude windborne dispersal is common yet under-appreciated in invasive insect species.
Mining the UniProtKB/Swiss-Prot database for antimicrobial peptides
Authors: Li Chenkai , Sutherland Darcy , Salehi Ali , Richter Amelia , Lin Diana , Aninta Sambina Islam , Ebrahimikondori Hossein , Yanai Anat , Coombe Lauren , Warren René L. , Kotkoff Monica , Hoang Linda M.N. , Helbing Caren C. , Birol Inanc
Published: May 2024

The ever-growing global health threat of antibiotic resistance is compelling researchers to explore alternatives to conventional antibiotics. Antimicrobial peptides (AMPs) are emerging as a promising solution to fill this need. Naturally occurring AMPs are produced by all forms of life as part of the innate immune system. High-throughput bioinformatics tools have enabled fast and large-scale discovery of AMPs from genomic, transcriptomic, and proteomic resources of selected organisms. Public protein sequence databases, comprising over 200 million records and growing, serve as comprehensive compendia of sequences from a broad range of source organisms. Yet, large-scalein silicoprobing of those databases for novel AMPs has never been reported. In the present study, we propose an AMP mining workflow to predict novel AMPs from the UniProtKB/Swiss-Prot database using the AMP prediction tool, AMPlify, as its discovery engine. Using this workflow, we identified 8,008 novel putative AMPs from all eukaryotic sequences in the database. Focusing on the practical use of AMPs as suitable antimicrobial agents with applications in the poultry industry, we prioritized 40 of those AMPs based on their similarities to known chicken AMPs in predicted structures. In our tests, 13 out of the 38 successfully synthesized peptides showed antimicrobial activity againstEscherichia coliand/orStaphylococcus aureus.
Identification of potential inflammation markers for outgrowth of cow’s milk allergy
Authors: Hendrickx Diana M , Long Mengyichen ,   PRESTO study team, Wopereis Harm , van der Molen Renate G , Belzer Clara
Published: May 2024

Introduction

Immunoglobulin E (IgE)-mediated cow’s milk allergy (CMA) is an immune-mediated reaction to cow’s milk (CM). Non-IgE-mediated CMA resolves in most children in the first years of life, whereas IgE-mediated CMA outgrowth is often later or not at all. The exact mechanisms underlying resolution of IgE-mediated CMA are not fully understood.

Methods

We aim to gain insight in the immunological mechanisms underlying resolution of IgE-mediated CMA by analyzing unique saliva samples of allergic infants using the Olink® Target 96 Inflammation panel. Twenty-four children who outgrew their CMA after 12 months were compared to 15 with persistent CMA.

Results

Persistent CMA was accompanied by an increase in interleukin-15 receptor subunit alpha in the first 6 months, followed by a decrease, hinting towards an initial increased T cell response. At the same time caspase-8 was increased and interleukin-7 was decreased in persistent CMA. For CMA resolution, we found elevated levels of delta and notch-like epidermal growth factor-related receptor. Furthermore, adenosine deaminase (ADA) increased significantly between 0 and 12 months in resolved CMA, but not in persistent CMA. KEGG pathway analysis suggests mainly the TNF signaling pathway to be important in the resolution of CM allergy.

Conclusion

Olink® Target 96 Inflammation panel analysis of saliva samples can reveal potential immunological markers and mechanisms involved in CMA resolution.
On forensic likelihood ratios from low-coverage sequencing
Authors: Ouerghi Feriel , Krane Dan E. , Edge Michael D.
Published: May 2024

Advances in sequencing technology are allowing forensic scientists to access genetic information from increasingly challenging samples. A recently published computational approach,IBDGem, analyzes sequencing reads, including from low-coverage samples, in order to arrive at likelihood ratios for human identification. Here, we show that likelihood ratios produced byIBDGemare best interpreted as testing a null hypothesis different from the traditional one used in a forensic genetics context. In particular, rather than testing the hypothesis that the sample comes from a person unrelated to the person of interest,IBDGemtests the hypothesis that the sample comes from an individual who is included in the reference database used to run the method. This null hypothesis is not generally of forensic interest, because the defense hypothesis is not typically that the evidence comes from an individual included in a reference database. Moreover, the computed likelihood ratios can be much larger than likelihood ratios computed for the standard forensic null hypothesis, often by many orders of magnitude, thus potentially creating an impression of stronger evidence for identity than is warranted. We lay out this result and illustrate it with examples, giving suggestions for directions that might lead to likelihood ratios that test the typical defense hypothesis.
Overlapping coactivator function is required for transcriptional activation by theCandida glabrataPdr1 transcription factor
Authors: Conway Thomas P. , Simonicova Lucia , Moye-Rowley W. Scott
Published: May 2024

Azole resistance in the pathogenic yeastCandida glabratais a serious clinical complication and increasing in frequency. The majority of resistant organisms have been found to contain a substitution mutation in the Zn2Cys6 zinc cluster-containing transcription factor Pdr1. These mutations typically lead to this factor driving high, constitutive expression of target genes like the ATP-binding cassette transporter-encoding geneCDR1. Overexpression of Cdr1 is required for the observed elevated fluconazole resistance exhibited by strains containing one of these hyperactivePDR1alleles. While the identity of hyperactivePDR1alleles has been extensively documented, the mechanisms underlying how these gain-of-function (GOF) forms of Pdr1 lead to elevated target gene transcription are not well understood. We have used a tandem affinity purification (TAP)-tagged form of Pdr1 to identify coactivator proteins that biochemically purify with the wild-type and two different GOF forms of Pdr1. Three coactivator proteins were found to associate with Pdr1: the SWI/SNF complex Snf2 chromatin remodeling protein and two different components of the SAGA complex, Spt7 and Ngg1. We found that deletion mutants lacking eitherSNF2orSPT7exhibited growth defects, even in the absence of fluconazole challenge. To overcome these issues, we employed a conditional degradation system to acutely deplete these coactivators and determined that loss of either coactivator complex, SWI/SNF or SAGA, caused defects in Pdr1-dependent transcription. A double degron strain that could be depleted for both SWI/SNF and SAGA exhibited a profound defect inPDR1autoregulation, revealing that these complexes work together to ensure high level Pdr1-dependent gene transcription.
Cell-specific nanoengineering strategy disrupts tolerogenic signaling from myeloid-derived suppressor cells to invigorate antitumor immunity in pancreatic cancer
Authors: Deshpande Nilesh U. , Bianchi Anna , Amirian Haleh , De Castro Silva Iago , Rafie Christine I. , Surnar Bapurao , Rajkumar Karthik , Ogobuiro Ifeanyichukwu C. , Patel Manan , Mehra Siddharth , Nagathihalli Nagaraj S. , Merchant Nipun B. , Dhar Shanta , Datta Jashodeep
Published: May 2024

Pancreatic ductal adenocarcinoma (PDAC) is characterized by intratumoral abundance of neutrophilic/polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) which inhibit T-cell function through JAK2/STAT3-regulated arginase activity. To overcome limitations of systemic inhibition of PMN-MDSCs in cancer-bearing patients—i.e., neutropenia and compensatory myelopoietic adaptations—we develop a nanoengineering strategy to target cell-specific signaling exclusively in PMN-MDSCs without provoking neutropenia. We conjugate a chemically modified small-molecule inhibitor of MDSC-surface receptor CXCR2 (AZD5069) with polyethylene glycol (PEG) and chemically graft AZD5069-PEG constructs onto amphiphilic polysaccharide derivatives to engineer CXCR2-homing nanoparticles (CXCR2-NP). Cy5.5 dye-loaded CXCR2-NP showed near-exclusive uptake in PMN-MDSCs compared with PDAC tumor-cells, cancer-associated fibroblasts, and macrophages. Encapsulation of JAK2/STAT3i Ruxolitinib (CXCR2-NPRuxo) resulted in more durable attenuation in STAT3-regulated arginase activity from PMN-MDSCs and induction of cytolytic T-cell activity vs. free Ruxolitinibin-vitroandin-vivo. Cell-specific delivery of payloads via CXCR2-homing immunonanoparticles represents a novel strategy to disrupt MDSC-mediated immunosuppression and invigorate antitumor immunity in PDAC.
Evolutionary trajectories of resistant mutants during sub-MIC antibiotic exposure
Authors: Warsi Omar M.
Published: May 2024

The emergence of antibiotic resistance is one of the most important examples of contemporary evolution. Selection for resistance can occur over a wide concentration range, both above and below the minimum inhibitory concentration (MIC) of the antibiotic. In a majority of cases, resistance mutations confer fitness costs and several studies have shown the importance of these costs for the emergence, ascendance and maintenance of resistance in a population. Importantly, these costs can often be ameliorated by compensatory mutations and rate and efficiency of compensation is a key parameter in determining the evolutionary success of a costly resistance mutation. Despite this knowledge, we still have a limited understanding of how resistance evolution (to increase resistance) and compensatory evolution (to reduce fitness costs) interact during growth in presence of low, sub-MIC, antibiotic concentrations. To examine the impact of these two processes, we carried out evolution experiments at sub-MIC levels of streptomycin using twoE. colimutants (with loss of function mutations in theselBandubiHgenes, respectively) that show low-level streptomycin resistance, and have different fitness costs. For both mutants, evolution at sub-MIC levels enriched for mutations that increased resistance, but selection for compensatory mutations was also common over the course of the experiment. Our study highlights that costly low-level resistant mutants adapt to sub-MIC antibiotic exposure by either increasing resistance, reducing cost or both and that this evolution can result in the maintenance of these mutants in the population.
diaTracer enables spectrum-centric analysis of diaPASEF proteomics data
Authors: Li Kai , Teo Guo Ci , Yang Kevin L. , Yu Fengchao , Nesvizhskii Alexey I.
Published: May 2024

Data-independent acquisition (DIA) has become a widely used strategy for peptide and protein quantification in mass spectrometry-based proteomics studies. The integration of ion mobility separation into DIA analysis, such as the diaPASEF technology available on Bruker’s timsTOF platform, further improves the quantification accuracy and protein depth achievable using DIA. We introduce diaTracer, a new spectrum-centric computational tool optimized for diaPASEF data. diaTracer performs three-dimensional (m/z, retention time, ion mobility) peak tracing and feature detection to generate precursor-resolved “pseudo-MS/MS” spectra, facilitating direct (“spectral-library free”) peptide identification and quantification from diaPASEF data. diaTracer is available as a stand-alone tool and is fully integrated into the widely used FragPipe computational platform. We demonstrate the performance of diaTracer and FragPipe using diaPASEF data from triple-negative breast cancer (TNBC), cerebrospinal fluid (CSF), and plasma samples, data from phosphoproteomics and HLA immunopeptidomics experiments, and low-input data from a spatial proteomics study. We also show that diaTracer enables unrestricted identification of post-translational modifications from diaPASEF data using open/mass-offset searches.
Aquatic metabolism throughout impoundment of a low productivity boreal reservoir using free water oxygen
Authors: Gedig Daniel P , Soloway Ashley D , Gill Robert , Papakyriakou Tim N
Published: May 2024

Inland water bodies play a significant role in the global cycling of greenhouse gases (GHGs). Impoundment of rivers changes their GHG dynamics and leads to a pulse of emissions, primarily due to the respiration of introduced organic matter (OM). Aquatic metabolism estimates using free water oxygen curves were calculated at five sites on the lower Nelson River, Manitoba, Canada to assess the impact of impounding a new hydroelectric reservoir at the Keeyask Generating Station. After impoundment, the greatest ecosystem respiration (R) rates were seen in a former tributary inflow (-1.94 ± 1.03 g C m-2d-1) and then in the forebay (-1.06 ± 0.74 g C m-2d-1), an order of magnitude greater than the upstream extent of the reservoir area that appeared unimpacted (-0.13 ± 0.29 g C m-2d-1). Benthic and pelagic R were of greater relative importance in the former tributary inflow and the forebay, respectively. Loading of allochthonous OM was a key factor regulating R. Further, evidence of "priming," wherein labile OM facilitates the breakdown of more recalcitrant OM, was observed. Light limitation appeared to be prevalent throughout the study area, consistent with previous studies in the region. Despite the unique water chemistry present (i.e., high total phosphorus, high turbidity), aquatic metabolism in the study area appeared similar to other boreal impoundments. The results presented here updated the understanding of aquatic metabolism in a region characterized by hydroelectric development. Further, challenges in the methodology (e.g., gas transfer velocity estimation) were identified and discussed.
Suppression of autophagy induces senescence in the heart
Authors: Zhai Peiyong , Sung Eun-Ah , Shiheido-Watanabe Yuka , Takayama Koichiro , Tian Yimin , Sadoshima Junichi
Published: May 2024

Aging is a critical risk factor for heart disease, including ischemic heart disease and heart failure. Cellular senescence, characterized by DNA damage, resistance to apoptosis and the senescence-associated secretory phenotype (SASP), occurs in many cell types, including cardiomyocytes. Senescence precipitates the aging process in surrounding cells and the organ through paracrine mechanisms. Generalized autophagy, which degrades cytosolic materials in a non-selective manner, is decreased during aging in the heart. This decrease causes deterioration of cellular quality control mechanisms, facilitates aging and negatively affects lifespan in animals, including mice. Although suppression of generalized autophagy could promote senescence, it remains unclear whether the suppression of autophagy directly stimulates senescence in cardiomyocytes, which, in turn, promotes myocardial dysfunction in the heart. We addressed this question using mouse models with a loss of autophagy function.

Suppression of general autophagy in cardiac-specificAtg7knockout (Atg7cKO) mice caused accumulation of senescent cardiomyocytes. Induction of senescence via downregulation ofAtg7was also observed in chimericAtg7cardiac-specific KO mice and cultured cardiomyocytesin vitro, suggesting that the effect of autophagy suppression upon induction of senescence is cell autonomous. ABT-263, a senolytic agent, reduced the number of senescent myocytes and improved cardiac function inAtg7cKO mice. Suppression of autophagy and induction of senescence were also observed in doxorubicin-treated hearts, where activation of autophagy alleviated senescence in cardiomyocytes and cardiac dysfunction. These results suggest that suppression of general autophagy directly induces senescence in cardiomyocytes, which in turn promotes cardiac dysfunction.
Multiwell-based G0-PCC assay for radiation biodosimetry
Authors: Royba Ekaterina , Shuryak Igor , Ponnaiya Brian , Repin Mikhail , Pampou Sergey , Karan Charles , Turner Helen , Garty Guy , Brenner David J.
Published: May 2024

In cytogenetic biodosimetry, assessing radiation exposure typically requires over 48 hours for cells to reach mitosis, significantly delaying the administration of crucial radiation countermeasures needed within the first 24 hours post-exposure. To improve medical response times, we incorporated the G0-Premature Chromosome Condensation (G0-PCC) technique with the Rapid Automated Biodosimetry Tool-II (RABiT-II), creating a faster alternative for large-scale radiation emergencies. Our findings revealed that using a lower concentration of Calyculin A (Cal A) than recommended effectively increased the yield of highly-condensed G0-PCC cells (hPCC). However, integrating recombinant CDK1/Cyclin B kinase, vital for chromosome condensation, proved challenging due to the properties of these proteins affecting interactions with cellular membranes. Interestingly, Cal A alone was capable of inducing chromosome compaction in some G0 cells even in the absence of mitotic kinases, although these chromosomes displayed atypical morphologies. This suggests that Cal A mechanism for compacting G0 chromatin may differ from condensation driven by mitotic kinases. Additionally, we observed a correlation between radiation dose and extent of hPCC chromosome fragmentation, which allowed us to automate radiation damage quantification using a Convolutional Neural Network (CNN). Our method can address the need for a same-day cytogenetic biodosimetry test in radiation emergency situations.
Deep learning-based cytoskeleton segmentation for accurate high-throughput measurement of cytoskeleton density
Authors: Horiuchi Ryota , Kamimura Asuka , Hanaki Yuga , Matsumoto Hikari , Ueda Minako , Higaki Takumi
Published: May 2024

Microscopic analyses of cytoskeleton organization are crucial for understanding various cellular activities, including cell proliferation and environmental responses in plants. Traditionally, assessments of cytoskeleton dynamics have been qualitative, relying on microscopy-assisted visual inspection. However, the transition to quantitative digital microscopy has introduced new technical challenges, with segmentation of cytoskeleton structures proving particularly demanding. In this study, we examined the utility of a deep learning-based segmentation method for accurate quantitative evaluation of cytoskeleton organization using confocal microscopic images of the cortical microtubules in tobacco BY-2 cells. The results showed that, although conventional methods sufficed for measurement of cytoskeleton angles and parallelness, the deep learning-based method significantly improved the accuracy of density measurements. To assess the versatility of the method, we extended our analysis to physiologically significant models in the context of changes in cytoskeleton density, namelyArabidopsis thalianaguard cells and zygotes. The deep learning-based method successfully improved the accuracy of cytoskeleton density measurements for quantitative evaluations of physiological changes in both stomatal movement in guard cells and intracellular polarization in elongating zygotes, confirming its utility in these applications. The results demonstrate the effectiveness of deep learning-based segmentation in providing precise and high-throughput measurements of cytoskeleton density, and has the potential to automate and expedite analyses of large-scale image datasets.
Conceptual framework of episodic disability in the context of Long COVID: Findings from a community-engaged international qualitative study
Authors: O’Brien Kelly K. , Brown Darren A. , McDuff Kiera , St. Clair-Sullivan Natalie , Carusone Soo Chan , Thomson Catherine , McCorkell Lisa , Wei Hannah , Goulding Susie , O’Hara Margaret , Roche Niamh , Stokes Ruth , Kelly Mary , Cheung Angela M. , Erlandson Kristine M. , Harding Richard , Vera Jaime H. , Bergin Colm , Robinson Larry , Avery Lisa , Bannan Ciaran , Torres Brittany , O’Donovan Imelda , Malli Nisa , Solomon Patricia
Published: May 2024

Background

Increasing numbers of adults are living with the health-related consequences of Long COVID. The Episodic Disability Framework (EDF), derived from perspectives of adults living with HIV, characterizes the multidimensional and episodic nature of health-related challenges (disability) experienced by an individual. Our aim was to determine the applicability of the Episodic Disability Framework to conceptualize the health-related challenges experienced among adults living with Long COVID.

Methods

We conducted a community-engaged qualitative descriptive study involving online semi-structured interviews. We recruited adults who self-identified as living with Long COVID via collaborator community organizations in Canada, Ireland, United Kingdom, and United States. We purposively recruited for diversity in age, gender identity, ethnicity, sexual orientation, and time since initial COVID-19 infection. We used a semi-structured interview guide informed by the EDF to explore experiences of disability living with Long COVID, specifically health-related challenges and how challenges were experienced over time. We conducted a group-based content analysis.

Results

Of the 40 participants, the median age was 39 years; and the majority were white (73%), women (63%), living with Long COVID for ≥1 year (83%). Consistent with the Episodic Disability Framework, disability was described as multidimensional and episodic, characterized by unpredictable periods of health and illness. Experiences of disability were consistent with the three main components of the Framework: A) dimensions of disability (physical, cognitive, mental-emotional health challenges, difficulties with day-to-day activities, challenges to social inclusion, uncertainty); B) contextual factors, extrinsic (social support; accessibility of environment and health services; stigma and epistemic injustice) and intrinsic (living strategies; personal attributes) that exacerbate or alleviate dimensions of disability; and C) triggers that initiate episodes of disability.

Conclusions

The Episodic Disability Framework provides a way to conceptualize disability the multidimensional and episodic nature of disability experienced by adults living with Long COVID. The Framework provides guidance for future measurement of disability, and health and rehabilitation approaches to enhance practice, research, and policy in Long COVID.
Competition effects regulating the composition of the microRNA pool
Authors: Raak Sofia B. , Hanley Jonathan G. , O’Donnell Cian
Published: May 2024

MicroRNAS (miRNAs) are short non-coding RNAs that can repress mRNA translation to regulate protein synthesis. During their maturation, multiple types of pre-miRNAs compete for a shared pool of the enzyme Dicer. It is unknown how this competition for a shared resource influences the relative expression of mature miRNAs. We study this process in a computational model of pre-miRNA maturation, fitted toin vitroDrosophila S2 cell data. We find that those pre-miRNAs which efficiently interact with Dicer outcompete other pre-miRNAs, when Dicer is scarce. To test our model predictions, we re-analysed previously publishedex vivomouse striatum data with reducedDicer1expression. We calculated a proxy measure for pre-miRNA affinity to TRBP (a protein which loads pre-miRNAs to Dicer). This measure well-predicted mature miRNA levels in the data, validating our assumptions. We used this as a basis to test the the model’s predictions through further analysis of the data. We found that pre-miRNAs with strong TRBP association are over-represented in competition conditions, consistent with the modelling. Finally using further simulations, we discovered that pre-miRNAs with low maturation rates can affect the mature miRNA pool via competition among pre-miRNAs. Overall, this work presents evidence of pre-miRNA competition regulating the composition of mature miRNAs.
Bayes Factor for Linear Mixed Model in Genetic Association Studies
Authors: Guan Yongtao , Levy Daniel
Published: May 2024

Motivation

Bayes factor has advantages over p-value as test statistics for association, particularly when comparing multiple alternative models. A software package to compute Bayes factor for linear mixed model is lacking.

Results

We transformed the standard linear mixed model as Bayesian linear regression, substituting the random effect by fixed effects with eigenvectors as covariates whose prior effect sizes are proportional to their corresponding eigenvalues. Using conjugate normal inverse gamma priors on regression parameters, Bayes factors can be computed in a closed form. We then showed that the transformed Bayesian linear regression produced identical estimates to those of the best linear unbiased prediction (BLUP), providing a new derivation to a known connection between BLUP and Bayesian estimates.

Availability and implementation

Methods described in this note are implemented in the software IDUL as two new functionalities: computing Bayes factors and residuals for the linear mixed model. IDUL and its source code are freely available athttps://github.com/haplotype/idul.
The epithelial adherens junction component PLEKHA7 regulates ECM remodeling and cell behavior through miRNA-mediated regulation of MMP1 and LOX
Authors: Daulagala Amanda C. , Cetin Metin , Nair-Menon Joyce , Jimenez Douglas W. , Bridges Mary Catherine , Bradshaw Amy D. , Sahin Ozgur , Kourtidis Antonis
Published: May 2024

Epithelial adherens junctions (AJs) are cell-cell adhesion complexes that are influenced by tissue mechanics, such as those emanating from the extracellular matrix (ECM). Here, we introduce a mechanism whereby epithelial AJs can also regulate the ECM. We show that the AJ component PLEKHA7 regulates levels and activity of the key ECM remodeling components MMP1 and LOX in well-differentiated colon epithelial cells, through the miR-24 and miR-30c miRNAs. PLEKHA7 depletion in epithelial cells results in LOX-dependent ECM remodeling in culture and in the colonic mucosal lamina propria in mice. Furthermore, PLEKHA7-depleted cells exhibit increased migration and invasion rates that are MMP1- and LOX-dependent, and form colonies in 3D cultures that are larger in size and acquire aberrant morphologies in stiffer matrices. These results reveal an AJ-mediated mechanism, through which epithelial cells drive ECM remodeling to modulate their behavior, including acquisition of phenotypes that are hallmarks of conditions such as fibrosis and tumorigenesis.

Teaser

Epithelial cells instruct ECM remodeling to modulate their behavior, as a result of adherens junction and miRNA disruption.
Protective effect of P2Y receptors antagonism on stress-induced retinal degeneration
Authors: Bao Yi , Bond Kyle , Sarraf Pauline , Esterberg Robert , Serpa Megan , Twarog Michael , Xu YongYao , MacLeod Heather , Huang Qian , Saint-Geniez Magali
Published: May 2024

The death of retinal pigment epithelial (RPE) cells and photoreceptors (PR) is a hallmark of the progression of several degenerative ocular disorders. The precise molecular driver(s) behind RPE and PR cell death, however, remains unknown. Recent studies have suggested the involvement of ATP and purinergic signaling in the progression of age-related macular degeneration (AMD) and retinal degeneration. We have discovered that RPE cells release ATP when subjected to stress, which in turn exacerbates stress-related signaling via purinergic receptors that ultimately results in degeneration. Our findings demonstrate that blocking P2Y purinergic receptors using suramin can effectively prevent toxin-induced RPE cell death and dysfunctionin vitro. Furthermore, we show efficacy of suramin in preventing photoreceptor degenerationin vivousing the RHO-P23H zebrafish model. This study reinforces the involvement of ATP and purinergic signaling in maintaining retinal health, and highlights the potential of purinergic receptor antagonism as a therapeutic strategy for retinal degeneration.
FICD deficiency protects mice from hypertrophy-induced heart failure via BiP-mediated activation of the UPRERand ER-phagy
Authors: Lacy Shannon M. , Taubitz Rebecca J. , Urban Nicholas D. , Turowski Samantha N. , Smith Eric D. , Helms Adam S. , Michele Daniel E. , Truttmann Matthias C.
Published: May 2024

Cardiomyocytes require the HSP70 chaperone BiP to maintain proteostasis in the endoplasmic reticulum (ER) following cardiac stress. The adenylyl transferase (AMPylase) FICD is increasingly recognized to regulate BiP activity through the post-translational addition of an adenosine monophosphate moiety to BiP surface residues. However, the physiological impact of FICD-mediated BiP regulation in the context of cardiovascular health is unknown. Here, we find that FICD deficiency prevents pressure overload-associated heart failure, hypertrophy, and fibrosis, and that FICD knockout mice maintain normal cardiac function after cardiac pressure overload. At a cellular level, we observe that FICD-mediated BiP AMPylation blunts the induction of the unfolded protein response (UPRER) and impairs BiP interaction with FAM134B, an ER-phagy receptor, thus limiting ER-phagy induction under stress. In contrast, FICD loss significantly increases BiP-dependent UPRERinduction and ER-phagy in stressed cardiomyocytes. We also uncover cell type-specific consequences of FICD activity in response to ER stress, positioning FICD as a critical proteostasis regulator in cardiac tissue. Our results highlight a novel regulatory paradigm controlling stress resilience in cardiomyocytes and offer a rationale to consider FICD as a therapeutic target to treat cardiac hypertrophy.
Gram-positive bacteria are primed for surviving lethal doses of antibiotics and chemical stress
Authors: Guha Manisha , Singh Abhyudai , Butzin Nicholas C.
Published: May 2024

Antibiotic resistance kills millions worldwide yearly. However, a major contributor to recurrent infections lies in a small fraction of bacterial cells, known as persisters. These cells are not inherently antibiotic-resistant, yet they lead to increased antibiotic usage, raising the risk of developing resistant progenies. In a bacterial population, individual cells exhibit considerable fluctuations in their gene expression levels despite being cultivated under identical, stable conditions. This variability in cell-to-cell characteristics (phenotypic diversity) within an isogenic population enables persister cells to withstand antibiotic exposure by entering a non-dividing state. We recently showed the existence of “primed cells” inE. coli. Primed cells are dividing cells prepared for antibiotic stress before encountering it and are more prone to form persisters. They also pass their “prepared state” down for several generations through epigenetic memory. Here, we show that primed cells are common among distant bacterial lineages, allowing for survival against antibiotics and other chemical stress, and form in different growth phases. They are also responsible for increased persister levels in transition and stationary phases compared to the log phase. We tested and showed that the Gram-positive bacteriumBacillus megaterium, evolutionarily very distant from E. coli, forms primed cells and has a transient epigenetic memory that is maintained for 7 generations or more. We showed this using ciprofloxacin and the non-antibiotic chemical stress fluoride. It is well established that persister levels are higher in the stationary phase than in the log phase, and B. megaterium persisters levels are nearly identical from the early to late-log phase but are ∼2-fold and ∼4-fold higher in the transition and stationary phase, respectively. It was previously proposed that there are two distinct types of persisters: Type II forms in the log phase, while Type I forms in the stationary phase. However, we show that primed cells lead to increased persisters in the transition and stationary phase and found no evidence of Type I or II persisters with distant phenotypes. Overall, we have provided substantial evidence of the importance of primed cells and their transitory epigenetic memories to surviving stress.
Transcriptomic signatures and network-based methods uncover new Senescent Cell Anti-Apoptotic Pathways and Senolytics
Authors: Olascoaga Samael , Konigsberg Mina , Espinal-Enríquez Jesús , Tovar Hugo , Matadamas-Martínez Félix , Pérez-Villanueva Jaime , López-Diazguerrero Norma Edith
Published: May 2024

Cellular senescence is an irreversible cell cycle arrest caused by various stressors that damage cells. Over time, senescent cells accumulate and contribute to the progression of multiple age-related degenerative diseases. It is believed that these cells accumulate partly due to their ability to evade programmed cell death through the development and activation of survival and anti-apoptotic resistance mechanisms; however, many aspects of how these survival mechanisms develop and activate are still unknown. By analyzing transcriptomic signature profiles generated by the LINCS L1000 project and using network-based methods, we identified various genes that could represent new senescence-related survival mechanisms. Additionally, employing the same methodology, we identified over 600 molecules with potential senolytic activity. Experimental validation of our computational findings confirmed the senolytic activity of Fluorouracil, whose activity would be mediated by a multi-target mechanism, revealing that its targets AURKA, EGFR, IRS1, SMAD4, and KRAS are new senescence-associated survival and anti-apoptotic resistance pathways. The development of these pathways could depend on the stimulus that induces cellular senescence. The SCAPs development and activation mechanisms proposed in this work offer new insights into how senescent cells survive. Identifying new anti-apoptotic resistance targets and drugs with potential senolytic activity paves the way for developing new pharmacological therapies to eliminate senescent cells selectively.

Graphical Abstract
Continuous quality improvement with a two-step strategy effective for large-scale SARS-CoV-2 screening at the Tokyo 2020 Olympic and Paralympic Games
Authors: Miyachi Hayato , Asai Satomi , Kuroki Rika , Omi Kazuya , Ikenoue Chiaki , Shimada Satoshi
Published: May 2024

The Tokyo 2020 Olympic Games (Games) were held during the height of the coronavirus disease 2019 (COVID-19) pandemic. In order to detect the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) early enough to contain the spread as well as to facilitate the timely arrival of athletes at their game venues, all participating athletes up to 14,000 staying in the Olympic Village were screened daily for the infection. Toward this aim, a two-step strategy was adopted comprising screening of self-collected saliva samples using a chemiluminescence enzyme immunoassay followed by confirmatory testing using polymerase chain reaction. The testing system was integrated with an information management system covering all steps. To ensure the accuracy of testing results, rigorous quality assurance measures and monitoring of performance/specimen quality were implemented. The chronological chart analysis was implemented to monitor the holistic process and to give feedback to improve the sampling. Nearly all test results for 418506 saliva samples were reported within 12 hours of sample collection, achieving the target mean turnaround time of 150 minutes for confirmatory testing. As a result, athlete activity and performance for the Games were ensured. The chronological chart confirmed that no athletes were retired due to a false-positive result and no infection clusters among athletes were identified. In conclusion, continuous quality improvement in the two-step strategy for the large-scale screening of COVID-19 contributed to the success of the Games during the pandemic. The quality practice, systems, and workflows described here may offer a model for future mass-gathering sporting events during similar major infectious disease epidemics.
Baseline immunotypes and immune entropy are indicators of multiple vaccine responsiveness
Authors: Cevirgel Alper , van der Heiden Marieke , Shetty Sudarshan A. , Viljanen Markus , Vos Martijn , Bijvank Elske , van Sleen Yannick , Imhof Celine , Rolwes Joeri A.J. , Samson Leonard Daniël , Beckers Lisa , Rots Nynke , van Beek Josine , Buisman Anne-Marie , van Baarle Debbie
Published: May 2024

Immune aging is associated with decreased vaccine responses, but biomarkers for vaccine responsiveness remain unidentified. We analyzed immunotypes describing baseline immune cell profiles and their associations with triple vaccine responsiveness to influenza, pneumococcal, and SARS-CoV-2 vaccines in adults aged 25-78 years. Additionally, we developed an innovative measure, immune entropy, to quantify cumulative perturbations in the immune cell subset network. Specific immunotypes associated with either weak or robust triple vaccine responsiveness. In addition, immune entropy was inversely related to vaccine responsiveness regardless of age. In a validation cohort of older adults, higher immune entropy was also associated with a lower antibody response to the BNT162b2 vaccine. A separate cohort of kidney transplant recipients, typically exhibiting diminished vaccine responses, demonstrated significantly increased immune entropy compared to healthy counterparts. Our findings suggest immunotypes and immune entropy as potential indicators to identify individuals at risk for suboptimal vaccine responses, potentially guiding personalized vaccination strategies.
No evidence of interaction betweenFADS2genotype and breastfeeding on cognitive or other traits in the UK Biobank
Authors: Centorame Giulio , Warrington Nicole M. , Hemani Gibran , Wang Geng , Davey Smith George , Evans David M.
Published: May 2024

Background

Breastfeeding is hypothesised to benefit child health and cognitive functioning by providing long-chain polyunsaturated fatty acids (LC-PUFA), which are essential for brain development. In 2007, Caspiet al.found evidence in two cohorts for an interaction between genetic variation in theFADS2gene (a gene involved in fatty acid metabolism) and breast feeding on IQ. However, subsequent studies have provided mixed evidence for the existence of an interaction.

Objective

To investigate the relationship between genetic variation in theFADS2region, breastfeeding, and their interaction on traits putatively affected by their interplay in a large, population-based cohort with appropriate control for confounders in genetic associations.

Methods

We tested for the interaction in up to 335,650 individuals from the UK Biobank, over a range of cognitive functioning tests, as well as educational attainment and other traits thought to be influenced by breastfeeding, including cardiometabolic traits, reproductive success, and atopic allergy.

Results

FADS2alleles associated with an increase in docosahexaenoic acid (DHA) in blood serum (the C allele of rs174575) were associated with decreased verbal-numerical reasoning (p=2.28× 10−5) and triglycerides (p=1. 40× 10−41), increased reproductive success (p=3. 40× 10−5), total cholesterol (p=5. 28× 10−36), HDL (p=1. 42× 10− 51), and LDL cholesterol (p=1. 46× 10− 21). We observed no evidence of an interaction in any of the traits, regardless of the modelling strategy.

Conclusions

We failed to replicate any breastfeeding by genotype interactions on any cognitive or non-cognitive traits. We postulate that the previous positive findings are likely to be spurious, perhaps due to lack of appropriate control for latent population structure.
Methylome-wide studies of six metabolic traits
Authors: Smith Hannah M. , Ng Hong Kiat , Moodie Joanna E. , Gadd Danni A. , McCartney Daniel L. , Bernabeu Elena , Campbell Archie , Redmond Paul , Taylor Adele , Page Danielle , Corley Janie , Harris Sarah E. , Tay Darwin , Deary Ian J. , Evans Kathryn L. , Robinson Matthew R. , Chambers John C. , Loh Marie , Cox Simon R. , Marioni Riccardo E. , Hillary Robert F.
Published: May 2024

Exploring the molecular correlates of metabolic health measures may identify the shared and unique biological processes and pathways that they track. Here, we performed epigenome-wide association studies (EWASs) of six metabolic traits: body mass index (BMI), body fat percentage, waist-hip ratio (WHR), and blood-based measures of glucose, high-density lipoprotein (HDL) cholesterol, and total cholesterol. We considered blood-based DNA methylation (DNAm) from >750,000 CpG sites in over 17,000 volunteers from the Generation Scotland (GS) cohort. Linear regression analyses identified between 304 and 11,815 significant CpGs per trait at P<3.6×10-8, with 37 significant CpG sites across all six traits. Further, we performed a Bayesian EWAS that jointly models all CpGs simultaneously and conditionally on each other, as opposed to the marginal linear regression analyses. This identified between 3 and 27 CpGs with a posterior inclusion probability ≥ 0.95 across the six traits. Next, we used elastic net penalised regression to train epigenetic scores (EpiScores) of each trait in GS, which were then tested in the Lothian Birth Cohort 1936 (LBC1936; European ancestry) and Health for Life in Singapore (HELIOS; Indian-, Malay- and Chinese-ancestries). A maximum of 27.1% of the variance in BMI was explained by the BMI EpiScore in the subset of Malay-ancestry Singaporeans. Four metabolic EpiScores were associated with general cognitive function in LBC1936 in models adjusted for vascular risk factors (Standardised βrange: 0.08 – 0.12, PFDR< 0.05). EpiScores of metabolic health are applicable across ancestries and can reflect differences in brain health.