bluuebunny/crossref_metadata_2025_split huggingface dataset:
The principles of expected and realised genetic relatedness among individual honeybees
Authors: Strachan Laura , Bubnič Jernej , Petersen Gertje , Gorjanc Gregor , Obsteter Jana 
Published: May 2024

AbstractMonitoring honeybee genetic variability is essential to manage global and local ge-netic diversity. Coefficients of relatedness are regularly used to measure genetic similar-ity within and between populations and their individuals. Although the haplo-diploid inheritance of honeybees is well understood, interpreting the various types of related-ness coefficients based on pedigree and genotype data is a challenge for researchers and practitioners in honeybee breeding. To demonstrate the principles of genetic relatedness in honeybees and its different individual-based estimators, we simulated three honeybee populations each containing 400 colonies over 10 years using the stochastic simulator SIMplyBee. We kept two populations closed and hybridised the third one by importing drones from one of the closed populations. We evaluated the relatedness between indi-viduals within a colony, between queens of the same population, and between queens of different populations. We calculated three types of relatedness: expected identity by descent using pedigree information, realised identity by descent using pedigree and genotype information, and identity by state using genotype information. Our results demonstrated an alignment of mean relatedness across different types when calculated using the same founder population, regardless of their data source. Identity by state relatedness varied significantly when calculated with different founder populations. Al-though this is an expected result, it shows that caution is needed when comparing values between studies using different populations with different allele frequencies. We expectedly showed increased relatedness over time in closed populations and decreased in the hybrid population. Our results underscore the significance of understanding the methodology for computing relatedness coefficients.
Model-based analysis of the circadian rhythm generation of bioluminescence reporter activity in duckweed
Authors: Horikawa Yu , Watanabe Emiri , Ito Shogo , Oyama Tokitaka 
Published: May 2024

AbstractBioluminescence monitoring techniques are widely used to study the gene expression dynamics in living plants. Monitoring the bioluminescence from a luciferase gene under the control of a circadian promoter is indispensable for examining plant circadian systems. The bioluminescence monitoring technique was successfully applied to physiological studies of circadian rhythms in duckweed plants. It has been reported that a luciferase gene under a constitutive promoter also exhibits a bioluminescent circadian rhythm in duckweed. However, the mechanisms underlying rhythm generation remain unknown. In this study, we performed a model-based analysis to evaluate the machinery that generates the bioluminescence rhythm. We hypothesized the rhythmic factor of three aspects regarding the bioluminescence intensities of luciferase in cells: luminescence efficiency, production rate, and degradation rate. Theoretically, if the latter two are involved in rhythm generation, the difference in luciferase stability affects the amplitude and phase relations of the bioluminescence rhythm. Luciferase stability is irrelevant to these rhythm properties if only the luminescence efficiency is involved. First, we simulated the bioluminescence rhythms of two luciferases with different stabilities associated with each of three rhythmic factors. Luciferase stability was set based on the reported values for Emerald-luciferase and Emerald-luciferase-PEST. We then experimentally examined the bioluminescence rhythms of reporters of these luciferases driven by theCAULIFLOWER MOSAIC VIRUS 35Spromoter in the duckweedLemna japonica. Their circadian properties matched those obtained from the simulation of the luminescence efficiency. This supports the view that cells in duckweed show circadian changes in physiological conditions associated with the luciferase enzyme reaction.
Evolution of theCdk4/6–Cdkn2system in invertebrates
Authors: Yuki Shiori , Sasaki Shunsuke , Yamamoto Yuta , Murakami Fumika , Sakata Kazumi , Araki Isato 
Published: May 2024

AbstractThe cell cycle is driven by cyclin-dependent kinases (Cdks). The decision whether the cell cycle proceeds is made during G1 phase, when Cdk4/6 functions. Cyclin-dependent kinase inhibitor 2 (Cdkn2) is a specific inhibitor of Cdk4/6, and their interaction depends on D84 in Cdkn2 and R24/31 in Cdk4/6. This knowledge is based mainly on studies in mammalian cells. Here, we comprehensively analyzedCdk4/6andCdkn2in invertebrates and found thatCdk4/6was present in most of the investigated phyla, but the distribution ofCdkn2was rather uneven among and within the phyla. The positive charge of R24/R31 in Cdk4/6 was conserved in all analyzed species in phyla with Cdkn2. The presence ofCdkn2and the conservation of the positive charge were statistically correlated. We also found thatCdkn2has been tightly linked toFas associated factor 1(Faf1) during evolution. We discuss potential interactions between Cdkn2 and Cdk4/6 in evolution and the possible cause of the strong conservation of the microsynteny.
Arabidopsis terminal nucleotidyl transferases govern secondary siRNA production at distinct steps
Authors: Vigh Maria Louisa , Thieffry Axel , Arribas-Hernández Laura , Brodersen Peter 
Published: May 2024

ABSTRACTIn plants, RNA interference (RNAi) mediated by the endonucleolytic RNA-Induced Silencing Complex (RISC) defends against foreign RNA and regulates endogenous genes. Targeting of RISC to foreign RNA establishes amplification loops, wherein RNA-dependent RNA Polymerase 6 (RDR6) synthesizes double-stranded RNA (dsRNA) for secondary small interfering RNA (siRNA) biogenesis, using cleavage fragments of RNA targeted by RISC programmed with a primary siRNA as template. Secondary siRNA production from endogenous RISC targets requires a particular primary small RNA size or target site multiplicity. siRNA amplification in yeast and nematodes requires terminal nucleotidyl transferases (TNTases), but their roles in plants are unclear. Here, we demonstrate two functions of TNTases in siRNA amplification inArabidopsis thaliana. URT1 prevents initiation of microRNA-induced secondary siRNA formation through uridylation of 5’-cleavage fragments, sometimes redundantly with the exosome and the TNTase HESO1. Once initiated via RDR6 recruitment, HESO1 and other TNTases stimulate secondary siRNA formation by producing 2-nt 3’overhangs on RDR6-synthesized dsRNA to yield substrates for processing into siRNAs by DICER-LIKE4. These results define molecular mechanisms by which TNTases control siRNA amplification in plants.
PTGS is dispensable for the initiation of epigenetic silencing of an active transposon inArabidopsis
Authors: Trasser Marieke , Bohl-Viallefond Grégoire , Barragán-Borrero Verónica , Diezma-Navas Laura , Loncsek Lukas , Nordborg Magnus , Marí-Ordóñez Arturo 
Published: May 2024

AbstractTransposable elements (TEs) are largely repressed in plants through transcriptional gene silencing (TGS), which is maintained by heritable epigenetic silencing marks such as DNA methylation. However, the mechanisms by which silencing is installed in the first place remains poorly understood in plants. Small interfering (si)RNAs and post-transcriptional gene silencing (PTGS) play a role in the initial response by reducing mRNA and protein levels of active TEs and are believed to mediate the initiation of TGS by guiding the first deposition of DNA methylation. To determine how this silencing installation works, we took advantage ofÉVADÉ (EVD), an endogenous retroelement in Arabidopsis, which can be used to recapitulate truede novosilencing with a well-established sequence of PTGS followed by a TGS phase. To test whether PTGS is a prerequisite for TGS, activeEVDcopies were introduced into RNA-DEPENDENT-RNA-POLYMERASE-6 (RDR6) mutants lacking an essential PTGS component.EVDactivity and silencing were monitored across several generations. Unexpectedly, even in the absence of PTGS, TGS and silencing ofEVDwere still achieved through installation of RNA-directed DNA methylation (RdDM) atEVDregulatory sequences without any prior DNA methylation at its coding sequence. Hence, our study shows that PTGS is dispensable forde novo EVDsilencing. Although we cannot rule out that PTGS might facilitate the initiation of TGS, or control TE activity until then, initiation of epigenetic silencing can take place in its absence.
The endolysosomal phospholipid bis(monoacylglycero)phosphate is synthesized via intra- and extracellular pathways
Authors: Bulfon Dominik , Breithofer Johannes , Grabner Gernot F. , Fawzy Nermeen , Pirchheim Anita , Wolinski Heimo , Kolb Dagmar , Hartig Lennart , Tischitz Martin , Zitta Clara , Bramerdorfer Greta , Lass Achim , Taschler Ulrike , Kratky Dagmar , Greimel Peter , Zimmermann Robert 
Published: May 2024

AbstractBis(monoacylglycero)phosphate (BMP) is a major phospholipid constituent of intralumenal membranes in late endosomes/lysosomes, where it regulates the degradation and sorting of lipid cargo. Recent observations suggest that the Batten disease - associated protein CLN5 functions as lysosomal BMP synthase. Here, we show that transacylation reactions catalyzed by cytosolic and secreted enzymes enhance BMP synthesis independently of CLN5. The transacylases identified in this study are capable of acylating the precursor lipid phosphatidylglycerol (PG), generating acyl-PG, which is subsequently hydrolyzed to BMP. Extracellularly, acyl-PG and BMP are generated by endothelial lipase in cooperation with other serum enzymes of the pancreatic lipase family. The intracellular acylation of PG is catalyzed by several members of the cytosolic phospholipase A2 group IV (PLA2G4) family. Overexpression of secreted or cytosolic transacylases was sufficient to correct BMP deficiency in HEK293 cells lackingCLN5. Collectively, our observations suggest that functionally overlapping pathways promote BMP synthesis in mammalian cells.
Spatiotemporally resolved transcriptome atlas of developing mouse placenta reveals mechanisms of embryonic lethality
Authors: Fu Yuting , Zeng Xiaoqi , Liu Yifang , Jia Shikai , Jiang Yujia , Tan Jia Ping , Yuan Yue , Xia Tianchang , Mei Yun , Wen Shan , Liu Xiaojing , You Yue , Pei Weike , Yang Chengshuo , Shao Sida , Cheng Saifeng , Tian Luyi , Liu Longqi , Wei Xiaoyu , Liu Xiaodong 
Published: May 2024

SummaryProper placentation is essential for embryonic growth and viability, yet the spatial organization and interactions of placental cell types remain incompletely understood. Here, we present a spatiotemporal transcriptomic atlas of the mouse placenta (STAMP) from embryonic days 9.5 to 18.5 at single-cell resolution. This atlas delineates major placental cell types and developmental trajectories. We observed labyrinth region expansion through branching morphogenesis, with trophoblast progenitor cells declining and terminally differentiated trophoblast cells increasing from E12.5 onward, and glycogen cells (GCs) transitioned from the junctional zone (JZ) to the maternal decidua. Furthermore, we found two novel GC subclusters with distinct spatial distributions and molecular features. Analysis of defective placentas revealed an increased number of GCs and altered macrophage distribution in the labyrinth layer. Transmission electron microscopy and glycogen content examination confirmed sluggish glycogen breakdown, while macrophage accumulation correlated with tissue remodeling and immune responses. Our spatial transcriptomic analysis elucidates mechanisms underlying placental abnormalities and embryonic lethality. This atlas enhances understanding of mouse placental development, aids in identifying developmental defects and pathogenic causes in dysfunctional placentas, and provides valuable insights for optimizingin vitroembryo culture conditions.
Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies
Authors: Morgenstern Travis J. , Darko-Boateng Arden , Afriyie Emmanuel , Shanmugam Sri Karthika , Zhou Xinle , Choudhury Papiya , Desai Meera , Kass Robert S. , Clarke Oliver B. , Colecraft Henry M. 
Published: May 2024

AbstractTargeted recruitment of E3 ubiquitin ligases to degrade traditionally undruggable proteins is a disruptive paradigm for developing new therapeutics. Two salient limitations are that <2% of the ~600 E3 ligases in the human genome have been exploited to produce proteolysis targeting chimeras (PROTACs), and the efficacy of the approach has not been demonstrated for a vital class of complex multi-subunit membrane proteins— ion channels. NEDD4-1 and NEDD4-2 are physiological regulators of myriad ion channels, and belong to the 28-member HECT (homologous to E6AP C-terminus) family of E3 ligases with widespread roles in cell/developmental biology and diverse diseases including various cancers, immunological and neurological disorders, and chronic pain. The potential efficacy of HECT E3 ligases for targeted protein degradation is unexplored, constrained by a lack of appropriate binders, and uncertain due to their complex regulation by layered intra-molecular and posttranslational mechanisms. Here, we identified a nanobody that binds with high affinity and specificity to a unique site on the N-lobe of the NEDD4-2 HECT domain at a location physically separate from sites critical for catalysis— the E2 binding site, the catalytic cysteine, and the ubiquitin exosite— as revealed by a 3.1 Å cryo-electron microscopy reconstruction. Recruiting endogenous NEDD4-2 to diverse ion channel proteins (KCNQ1, ENaC, and CaV2.2) using a divalent (DiVa) nanobody format strongly reduced their functional expression with minimal off-target effects as assessed by global proteomics, compared to simple NEDD4-2 overexpression. The results establish utility of a HECT E3 ligase for targeted protein downregulation, validate a class of complex multi-subunit membrane proteins as susceptible to this modality, and introduce endogenous E3 ligase recruitment with DiVa nanobodies as a general method to generate novel genetically-encoded ion channel inhibitors.
Aging represses lung tumorigenesis and alters tumor suppression
Authors: Shuldiner Emily G. , Karmakar Saswati , Tsai Min K. , Hebert Jess D. , Tang Yuning J. , Andrejka Laura , Wang Minwei , Detrick Colin R. , Cai Hongchen , Tang Rui , Petrov Dmitri A. , Winslow Monte M. 
Published: May 2024

ABSTRACTMost cancers are diagnosed in persons over the age of sixty, but little is known about how age impacts tumorigenesis. While aging is accompanied by mutation accumulation — widely understood to contribute to cancer risk — it is also associated with numerous other cellular and molecular changes likely to impact tumorigenesis. Moreover, cancer incidence decreases in the oldest part of the population, suggesting that very old age may reduce carcinogenesis. Here we show that aging represses tumor initiation and growth in genetically engineered mouse models of human lung cancer. Moreover, aging dampens the impact of inactivating many, but not all, tumor suppressor genes with the impact of inactivating PTEN, a negative regulator of the PI3K/AKT pathway, weakened to a disproportionate extent. Single-cell transcriptomic analysis revealed that neoplastic cells from tumors in old mice retain many age-related transcriptomic changes, showing that age has an enduring impact that persists through oncogenic transformation. Furthermore, the consequences of PTEN inactivation were strikingly age-dependent, with PTEN deficiency reducing signatures of aging in cancer cells and the tumor microenvironment. Our findings suggest that the relationship between age and lung cancer incidence may reflect an integration of the competing effects of driver mutation accumulation and tumor suppressive effects of aging.
The Polygenic Score Catalog: new functionality and tools to enable FAIR research
Authors: Lambert Samuel A. , Wingfield Benjamin , Gibson Joel T. , Gil Laurent , Ramachandran Santhi , Yvon Florent , Saverimuttu Shirin , Tinsley Emily , Lewis Elizabeth , Ritchie Scott C. , Wu Jingqin , Canovas Rodrigo , McMahon Aoife , Harris Laura W. , Parkinson Helen , Inouye Michael 
Published: May 2024

AbstractPolygenic scores (PGS) have transformed human genetic research and have multiple potential clinical applications, including risk stratification for disease prevention and prediction of treatment response. Here, we present a series of recent enhancements to the PGS Catalog (www.PGSCatalog.org), the largest findable, accessible, interoperable, and reusable (FAIR) repository of PGS. These include expansions in data content and ancestral diversity as well as the addition of new features. We further present the PGS Catalog Calculator (pgsc_calc,https://github.com/PGScatalog/pgsc_calc), an open-source, scalable and portable pipeline to reproducibly calculate PGS that securely democratizes equitable PGS applications by implementing genetic ancestry estimation and score normalization using reference data. With the PGS Catalog & calculator users can now quantify an individual’s genetic predisposition for hundreds of common diseases and clinically relevant traits. Taken together, these updates and tools facilitate the next generation of PGS, thus lowering barriers to the clinical studies necessary to identify where PGS may be integrated into clinical practice.
Leprosy stigma in the healthcare setting: The treatment-seeking journey of persons affected by Leprosy in Niger
Authors: Alio Amina P. , Mamane Sani Ibrahim Malam , Abdou Yohanna , Gado Moussa , Harouna Issa , Celiktemur Bahadir 
Published: May 2024

AbstractLeprosy-related stigma is deeply rooted in history and permeates every aspect of society, and stigmatization by healthcare professionals is no exception. This paper explores the experiences of persons affected by Leprosy with stigma in the healthcare setting throughout their treatment-seeking journey. We conducted one-on-one interviews with 112 individuals who experienced a Leprosy diagnosis and underwent treatment. Data was collected in July and August 2022, in 9 villages and 1 urban neighborhood in the region of Maradi, Niger. Over two-thirds of participants experienced some form of visible impairment due to Leprosy. Throughout their treatment-seeking journey, healthcare providers were reported to have stigmatized patients by using hurtful language, isolating patients, physically distancing from patients, or refusing to treat. The extent of the stigmatization depended on, first, whether Leprosy was recognized or not. Unfortunately, many healthcare providers did not detect the early signs of Leprosy, therefore, patients were then not able to obtain treatment prior to physical impairment. Second, the level of stigmatization varied based on the degree and type of visible physical impairments (e.g., missing fingers or toes, limbs, blindness). These negative experiences with healthcare workers made treatment-seeking and adherence to treatment regimen less likely for patients. Our findings confirm the presence of Leprosy stigma in the healthcare context in Niger. Increasing Leprosy knowledge and addressing stigma among healthcare professionals is key to early diagnosis and treatment of Leprosy.
Views and experiences of Antimicrobial Stewardship interventions in paediatric secondary care settings: A Qualitative Evidence Synthesis
Authors: Mate Nirzer , Vergnano Stefania , Cabral Christie 
Published: May 2024

ABSTRACTObjectivesInjudicious use of antimicrobial agents contributes to antimicrobial resistance. Antimicrobial Stewardship (AMS) interventions use strategies derived from evidence-based practices to ensure careful use of antibiotics. AMS is less common in paediatrics as compared to adult practice. As AMS success depends on organizational factors and individual behaviours, this study synthesizes the existing qualitative evidence exploring key barriers, facilitators, and acceptability of AMS.MethodsDesignA systematic search of primary qualitative studies was conducted in electronic databases.Data sourcesMEDLINE, PsychINFO via OVID, CINAHL electronic database and handsearching of grey literature sources was done.Eligibility criteriaQualitative studies exploring parents” and/or clinicians” (doctors and nurses) views, attitudes, beliefs, and knowledge on antimicrobial stewardship programmes in paediatric and neonatal hospitals.Data extraction and synthesisQuality appraisal was done using the Critical Appraisal Skills Programme (CASP) tool for qualitative studies. The extracted data was then synthesised by drawing on meta-ethnography.ResultsA total of 6 studies met the inclusion criteria. 5 studies reported the views and experiences of doctors and nurses, and 1 study reported those of parents. The perceived value of AMS differed in neonatal and paediatric contexts. Structural barriers like resource allocation and hospital organization were a barrier to implementation and acceptability. Nurses reported a lack of formal education about AMS as a barrier.Conclusion/ImplicationsThe factors affecting AMS in paediatric secondary care vary with the stakeholders in question. This review identifies some of the factors that can be used to formulate service-level AMS interventions and programmes.Strengths and limitations of the studyThis is the first evidence synthesis of the qualitative literature exploring the beliefs and experiences of parents and clinicians regarding paediatric AMS.The facilitators and barriers were identified from themes representative of all the included studies, increasing their validity.While included studies were conducted across six countries, all were within the developed world which could limit the generalisability of the findings.A limited number of studies was included due to limited number of primary studies conducted in this area.Original protocol from PROSPERORegistration number: CRD42022346842Available from:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022346842The process for data synthesis was changed from thematic analysis to meta-ethnography to accommodate the variety of ways in which the results were reported in the included studies.
Early changes in microRNA expression in Arabidopsis plants infected with the fungal pathogenFusarium graminearum
Authors: Ferreira Savio S. , Pandey Suman , Hemminger Jesseca , Bozdag Serdar , Antunes Mauricio S. 
Published: May 2024

AbstractPlants respond to biotic stressors by modulating various processes in an attempt to limit the attack by a pathogen or herbivore. Triggering these different defense processes requires orchestration of a network of proteins and RNA molecules that includes microRNAs (miRNAs). These short RNA molecules (20-22 nucleotides) have been shown to be important players in the early responses of plants to stresses because they can rapidly regulate the expression levels of a network of downstream genes. The ascomyceteFusarium graminearumis an important fungal pathogen that causes significant losses in cereal crops worldwide. Using the well-characterizedFusarium-Arabidopsispathosystem, we investigated how plants change expression of their miRNAs globally during the early stages of infection byF. graminearum. In addition to miRNAs that have been previously implicated in stress responses, we have also identified evolutionarily young miRNAs whose levels change significantly in response to fungal infection. Some of these young miRNAs have homologs present in cereals. Thus, manipulating expression of these miRNAs may provide a unique path toward development of plants with increased resistance to fungal pathogens.