bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epithelial Yap/Taz are required for functional alveolar regeneration following acute lung injury
Authors: DiGiovanni Gianluca T. , Han Wei , Sherrill Taylor , Taylor Chase J. , Nichols David S. , Geis Natalie M. , Singha Ujjal K. , Calvi Carla L. , Scott McCall A. , Dixon Molly M. , Lui Yang , Jang Ji-Hoon , Gutor Sergey S. , Polosukhin Vasiliy V. , Blackwell Timothy S. , Kropski Jonathan A. , Gokey Jason J. 
Published: June 2023

AbstractA hallmark of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases is dysregulated repair of the alveolar epithelium. The Hippo pathway effector transcription factors YAP and TAZ have been implicated as essential for type 1 and type 2 alveolar epithelial cell (AT1 and AT2) differentiation in the developing lung, yet aberrant activation of YAP/TAZ is a prominent feature of the dysregulated alveolar epithelium in IPF. In these studies, we sought to define the functional role of YAP/TAZ activity during alveolar regeneration. We demonstrate that Yap and Taz are normally activated in AT2 cells shortly after injury, and deletion of Yap/Taz in AT2 cells led to pathologic alveolar remodeling, failure of AT2 to AT1 cell differentiation, increased collagen deposition, exaggerated neutrophilic inflammation, and increased mortality following injury induced by a single dose of bleomycin. Loss of Yap/Taz activity prior to a LPS injury prevented AT1 cell regeneration, led to intra-alveolar collagen deposition, and resulted in persistent innate inflammation. Together these findings establish that AT2 cell Yap/Taz activity is essential for functional alveolar epithelial repair and prevention of fibrotic remodeling.
An uncanonical CDK6 activity inhibits cilia function by suppressing axoneme polyglutamylation
Authors: He Kai , Sun Xiaobo , Chen Chuan , Luc San , Hao Jielu , Zhang Yingyi , Huang Yan , Wang Haitao , Ling Kun , Hu Jinghua 
Published: June 2023

AbstractTubulin polyglutamylation is a post-translational modification that occurs primarily along the axoneme of cilia. Defective axoneme polyglutamylation impairs cilia function and has been correlated with ciliopathies, including Joubert Syndrome (JBTS). However, the precise mechanisms regulating proper axoneme polyglutamylation remain vague. Here, we show that Cyclin-Dependent Kinase 6 (CDK6), but not its paralog CDK4, localizes to cilia base and suppresses axoneme polyglutamylation by phosphorylating RAB11-interacting protein FIP5 at site S641, a critical regulator of cilia import of glutamylases. S641 phosphorylation disrupts the ciliary recruitment of FIP5 by impairing its association with RAB11, thereby reducing the ciliary import of glutamylases. Interestingly, significant upregulation of CDK6 and defective axoneme polyglutamylation were observed in Autosomal dominant polycystic kidney disease (ADPKD) cells. Encouragingly, the FDA-approved CDK4/6 inhibitor Abemaciclib can effectively restore cilia function in JBTS and ADPKD cells with defective glutamylation and suppresses renal cystogenesis in anex vivoADPKD model. In summary, our study elucidates regulatory mechanisms governing axoneme polyglutamylation and suggests developing CDK6-specific inhibitors could be a promising therapeutic strategy to enhance cilia function in ciliopathy patients.
PEO: Plant Expression Omnibus - a comparative transcriptomic database for 103 Archaeplastida
Authors: Koh Eugene , Goh William , Julca Irene , Villanueva Erielle , Mutwil Marek 
Published: June 2023

AbstractThe Plant Expression Omnibus (PEO) is a web application that provides biologists with access to gene expression insights across over 100 plant species, ∼60,000 manually annotated RNA-seq samples, and more than four million genes. The tool allows users to explore the expression patterns of genes across different organs, identify organ-specific genes, and discover top co-expressed genes for any gene of interest. PEO also provides functional annotations for each gene, allowing for the identification of genetic modules and pathways. PEO is designed to facilitate comparative kingdom-wide gene expression analysis and provide a valuable resource for plant biology research. We provide two case studies to demonstrate the utility of PEO in identifying candidate genes in pollen coat biosynthesis and investigating the biosynthetic pathway components of capsaicin inCapsicum annuum. The database is freely available athttps://expression.plant.tools/.
Pax3 and Pax7 function in combination with Mitf to generate melanophores and xanthophores in medaka and zebrafish
Authors: Miyadai Motohiro , Takada Hiroyuki , Shiraishi Akiko , Kimura Tetsuaki , Watakabe Ikuko , Kobayashi Hikaru , Nagao Yusuke , Naruse Kiyoshi , Higashijima Shin-ichi , Shimizu Takashi , Kelsh Robert N. , Hibi Masahiko , Hashimoto Hisashi 
Published: June 2023

AbstractNeural crest cells generate numerous derivatives, including pigment cells, and are a model for studying how fate specification from multipotent progenitors is controlled. In mammals, the core gene regulatory network (GRN) for melanocytes (their only pigment cell-type) contains three transcription factors Sox10, Pax3 and Mitf, with the latter considered a master regulator of melanocyte development. In teleosts, which have three to four pigment cell types (melanophores, iridophores and xanthophores, plus leucophores e.g. in medaka), GRNs governing fate specification are poorly understood, although Mitf function is considered conserved. Here, we show that the regulatory relationships between Sox10, Pax3 and Mitf are conserved in zebrafish, but the role for Mitf is more complex than previously emphasised, affecting xanthophore development too. Similarly, medaka Mitf is necessary for melanophore, xanthophore and leucophore formation. Furthermore, expression patterns and mutant phenotypes ofpax3andpax7suggest that Pax3 and Pax7 act sequentially, activatingmitfexpression. Pax7 modulates Mitf function, driving co-expressing cells to differentiate as xanthophores and leucophores rather than melanophores. We propose that pigment cell fate specification is better considered as resulting from the combinatorial activity of Mitf with other transcription factors.
First large-scale peach gene coexpression network: A new tool for predicting gene function
Authors: Pérez de los Cobos Felipe , García-Gómez Beatriz E. , Orduña-Rubio Luis , Batlle Ignasi , Arús Pere , Matus José Tomás , Eduardo Iban 
Published: June 2023

ABSTRACTTranscriptomics studies generate enormous amounts of biological information. Nowadays, representing this complex data as gene coexpression networks (GCNs) is becoming commonplace. Peach is a model for Prunus genetics and genomics, but identifying and validating genes associated to peach breeding traits is a complex task. A GCN capable of capturing stable gene-gene relationships would help researchers overcome the intrinsic limitations of peach genetics and genomics approaches and outline future research opportunities. In this study, we created the first large-scale GCN in peach, applying aggregated and non-aggregated methods to create four GCNs from 604 Illumina RNA-Seq libraries. We evaluated the performance of every GCN in predicting functional annotations using a machine-learning algorithm based on the ‘guilty-by-association’ principle. The GCN with the best performance was COO300, encompassing 21,956 genes and an average AUROC of 0.746. To validate its performance predicting gene function, we used two well-characterized genes involved in fruit flesh softening in peach: the endopolygalacturonasesPpPG21andPpPG22. Genes coexpressing withPpPG21andPpPG22were extracted and named as melting flesh (MF) subnetwork. Finally, we performed an enrichment analysis of MF subnetwork and compared the results with the current knowledge regarding peach fruit softening process. The MF subnetwork mainly included genes involved in cell wall expansion and remodeling, with expression triggered by ripening-related phytohormones such as ethylene, auxin and methyl jasmonates. All these processes are closely related with peach fruit softening and therefore related to the function ofPpPG21andPpPG22. These results validate COO300 as a powerful tool for peach andPrunusresearch. COO300, renamed as PeachGCN v1.0, and the scripts necessary to perform a function prediction analysis using it, are available athttps://github.com/felipecobos/PeachGCN.
The mechanism for polar localization of the type IVa pilus machine
Authors: Herfurth Marco , Pérez-Burgos María , Søgaard-Andersen Lotte 
Published: June 2023

AbstractType IVa pili (T4aP) are important for bacterial motility, adhesion, biofilm formation and virulence. This versatility is based on their cycles of extension, adhesion, and retraction. The conserved T4aP machine (T4aPM) drives these cycles, however the piliation pattern varies between species. To understand how these patterns are established, we focused on the T4aPM inMyxococcus xanthusthat assembles following an outside-in pathway, starting with the polar incorporation of the PilQ secretin forming a multimeric T4aP conduit in the outer membrane. We demonstrate that PilQ recruitment to the nascent poles initiates during cytokinesis, but most is recruited to the new poles in the daughters after completion of cytokinesis. This recruitment depends on the peptidoglycan-binding AMIN domains in PilQ. Moreover, the pilotin Tgl stimulates PilQ multimerization in the outer membrane, is transiently recruited to the nascent and new poles in a PilQ-dependent manner, and dissociates after completion of secretin assembly. Altogether, our data support a model whereby PilQ polar recruitment and multimerization occur in two steps: The PilQ AMIN domains bind septal and polar peptidoglycan, thereby enabling polar Tgl localization, which then stimulates secretin multimerization in the outer membrane. Using computational analyses, we provide evidence for a conserved mechanism of T4aPM pilotins whereby the pilotin transiently interacts with the unfolded β-lip, i.e. the region that eventually inserts into the outer membrane, of the secretin monomer. Finally, we suggest that the presence/absence of AMIN domain(s) in T4aPM secretins determines the different T4aPM localization patterns across bacteria.ImportanceType IVa pili (T4aP) are widespread bacterial cell surface structures with important functions in motility, surface adhesion, biofilm formation and virulence. Different bacteria have adapted different piliation patterns. To address how these patterns are established, we focused on the bipolar localization of the T4aP machine in the model organismM. xanthusby studying the localization of the PilQ secretin, the first component of this machine that assembles at the poles. Based on experiments using a combination of fluorescence microscopy, biochemistry and computational structural analysis, we propose that PilQ, and specifically its AMIN domains, binds septal and polar peptidoglycan, thereby enabling polar Tgl localization, which then stimulates PilQ multimerization in the outer membrane. We also propose that the presence and absence of AMIN domains in T4aP secretins determine the different piliation patterns across bacteria.
Cellular insights of beech leaf disease reveal abnormal ectopic cell division of symptomatic interveinal leaf areas
Authors: Vieira Paulo , Kantor Mihail R. , Jansen Andrew , Handoo Zafar A. , Eisenback Jonathan D. 
Published: June 2023

AbstractThe beech leaf disease nematode,Litylenchus crenataesubsp.mccannii,is recognized as a newly emergent nematode species that causes beech leaf disease (BLD) in beech trees (Fagusspp.) in North America. Changes of leaf morphology induced by BLD can provoke dramatic effects into the leaf architecture and consequently to tree performance and development. The initial symptoms of BLD appear as dark green interveinal banding patterns of the leaf. Despite the fast progression of this disease, the cellular mechanisms leading to the formation of such type of aberrant leaf phenotype remains totally unknown. To understand the cellular basis of BLD, we employed several microscopy approaches to provide an exhaustive characterization of nematode-infected buds and leaves. Histological sections revealed a dramatic cell change composition of these nematode-infected tissues. Diseased bud scale cells were typically hypertrophied and showed a high variability of size. Moreover, while altered cell division had no influence on leaf organogenesis, induction of cell proliferation on young leaf primordia led to a dramatic change in cell layer architecture. Hyperplasia and hypertrophy of the different leaf cell layers, coupled with an abnormal proliferation of chloroplasts specially in the spongy mesophyll cells, resulted in the typical interveinal leaf banding. These discrepancies in leaf cell structure were depicted by an abnormal rate of cellular division of the leaf interveinal areas infected by the nematode, promoting significant increase of cell size and leaf thickness. The formation of symptomatic BLD leaves is therefore orchestrated by distinct cellular processes, to enhance the value of these feeding sites and to improve their nutrition status to the nematode. These results revealed a high specialized mode of parasitism ofL. crenataesubsp.mccannii.
Exposure to the aryl hydrocarbon receptor agonist dioxin disrupts formation of the muscle, nerves, and vasculature in the developing jaw
Authors: Cintrón-Rivera Layra G. , Burns Nicole , Patel Ratna , Plavicki Jessica 
Published: June 2023

AbstractHuman exposures to environmental pollutants can disrupt embryonic development and impact juvenile and adult health outcomes by adversely affecting cell and organ function. Notwithstanding, environmental contamination continues to increase because of industrial development, insufficient regulations, and the mobilization of pollutants due to extreme weather events. Dioxins are a class of structurally related persistent organic pollutants that are highly toxic, carcinogenic, and teratogenic. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent dioxin compound and has been shown to induce toxic effects in developing organisms by activating the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor targeted by multiple persistent organic pollutants. Contaminant-induced AHR activation results in malformations in the craniofacial cartilages and neurocranium; however, the mechanisms mediating these phenotypes are not entirely understood. In this study, we utilized the optically transparent zebrafish model to elucidate novel transcriptional and structural targets of embryonic TCDD exposure leading to craniofacial malformations. To this end, we exposed zebrafish embryos at 4 hours post fertilization (hpf) to TCDD and employed a mixed-methods approach utilizing immunohistochemistry staining, transgenic reporter lines, fixed andin vivoconfocal imaging, and timelapse microscopy to determine the targets mediating TCDD-induced craniofacial phenotypes. Our data shows that embryonic TCDD exposure reduced jaw and pharyngeal arch Sox10+ chondrocytes and Tcf21+ pharyngeal mesoderm progenitors. Exposure to TCDD correspondingly led to a reduction in collagen type II deposition in Sox10+ domains. Embryonic TCDD exposure impaired development of tissues derived from or guided by Tcf21+ progenitors, namely: nerves, muscle, and vasculature. Specifically, TCDD exposure disrupted development of the hyoid and mandibular arch muscles, decreased neural innervation of the jaw, resulted in compression of cranial nerves V and VII, and led to jaw vasculature malformations. Collectively, these findings reveal novel transcriptional and structural targets of TCDD-induced toxicity, showcasing how contaminant exposures lead to congenital craniofacial malformations.HighlightsEmbryonic TCDD exposure diminishes Sox10+ craniofacial chondrocytes.Following TCDD exposure Col2a1 deposition is reduced in Sox10+ domains.Exposure to TCDD decreases Tcf21+ progenitors and impairs muscle formation.TCDD exposure leads to defects jaw innervation and cranial nerve establishment.Early TCDD exposure results in vasculature malformations in the jaw.Graphical Abstract
Characterization of the Oral Bacteriome of the Healthy Lewis Rat
Authors: Schramm Sareda TJ , DeCurtis Emily , Wheelis Sutton E. , Jorgeson Ian , Rodrigues Danieli BC , Palmer Kelli 
Published: June 2023

ABSTRACTRodents are the most frequently utilized animals forin vivoresearch, and rats are the most abundant rodent used to study peri-implantitis disease and progression. However, there are very few studies available that elucidate the healthy oral microbiome of rats. The aim of this study was to characterize the healthy oral bacteriome of the male Lewis rat at two unique niches, the gums and first molar, by sequencing the 16S rDNA v1-v3 region. We collected the microbiota of 12 male Lewis rats at the toothless alveolar crest and the first molar, on both sides of the mouth. We identified an average of 20,820 sequences per sample. There were no significant differences between the rat groups or sample sites in the diversity (α or β) of the bacteriome. A total of 359 amplicon sequence variants (ASVs) were identified in the bacteriome, correlating to the phylaFirmicutes,Actinobacteria,Proteobacteria, andBacteroidetes. Parallels exist at the genus level between human and rat oral bacteriomes, however, the overall diversity between comparable sites is lower in rats than humans. Similar findings were reached when using pooled or individual swab samples of rat mouths. This study characterizes two unique ecological niches within the healthy rat oral bacteriome and provides a baseline for comparison with future studies.IMPORTANCERats are frequently used for dental research, but little is known about their normal oral microbiota. Here, we use DNA sequence analysis to identify bacterial groups colonizing the rat mouth at the tooth surface and at the gums. This work contributes to our knowledge of bacterial diversity in the rat mouth.
snoRNA-guided tRNA 2’-O-methylation controls codon-biased gene expression and cellular states
Authors: Zhang Minjie , Li Kongpan , Bai Jianhui , Van Damme Ryan , Zhang Wei , Alba Mario , Stiles Bangyan L. , Chen Jian-Fu , Lu Zhipeng 
Published: June 2023

SUMMARYsnoRNAs are a large family of noncoding (nc)RNAs present across eukaryotes and archaea. While a subset of them guide 2’-O- methylation (Nm) and pseudouridylation (Ψ) of rRNAs and snRNAs, targets of most snoRNAs remain unknown. Here we used PARIS2 to map snoRNA targets, revealing an extensive and conserved snoRNA-tRNA interaction network. Using optimized denatured RiboMeth-seq (dRMS), we discovered snoRNA-guided Nm sites in ncRNAs, including tRNAs. Loss of snoRNAs and their associated 2’-O-methyltransferase FBL reduced tRNA modifications and increased fragmentation. CRISPR knockout of the D97/D133 family of snoRNAs reduced the activity and levels of several target tRNAs, including elongator (e)Met-CAU, leading to codon-biased transcriptome and translatome in human cells. The codon-biased gene expression tipped the balance between the dichotomous cellular states of proliferation and differentiation, and skewed germ layer potential of mouse embryonic stem cells. Together, we discovered a snoRNA-guided tRNA modification mechanism controlling codon-biased gene expression and cellular states.
Structural Basis for Autoinhibition by the Dephosphorylated Regulatory Domain of Ycf1
Authors: Khandelwal Nitesh Kumar , Tomasiak Thomas M. 
Published: June 2023

AbstractYeast Cadmium Factor 1 (Ycf1) sequesters glutathione and glutathione-heavy metal conjugates into yeast vacuoles as a cellular detoxification mechanism. Ycf1 belongs to the C subfamily of ATP Binding Cassette (ABC) transporters characterized by long flexible linkers, notably the regulatory domain (R-domain). R-domain phosphorylation is necessary for activity, whereas dephosphorylation induces autoinhibition through an undefined mechanism. Because of its transient and dynamic nature, no structure of the dephosphorylated Ycf1 exists, limiting understanding of this R-domain regulation. Here, we capture the dephosphorylated Ycf1 using cryo-EM and show that the unphosphorylated R-domain indeed forms an ordered structure with an unexpected helix-strand hairpin topology bound within the Ycf1 substrate cavity. This architecture and binding mode resemble that of a viral peptide inhibitor of an ABC transporter and the secreted bacterial WXG peptide toxins. We further reveal the subset of phosphorylation sites within the hairpin turn that drive the reorganization of the R-domain conformation, suggesting a mechanism for Ycf1 activation by phosphorylation-dependent release of R-domain mediated autoinhibition.
The HPV8 E6 protein targets the Hippo and Wnt signaling pathways as part of its arsenal to restrain keratinocyte differentiation
Authors: Wu Sharon C. , Grace Miranda , Munger Karl 
Published: June 2023

ABSTRACTInfections with β-genus HPVs cause hyperplastic cutaneous lesions. In individuals with the rare hereditary skin disease, epidermodysplasia verruciformis, such lesions can progress to cutaneous squamous cell carcinomas (cSCC). β-HPV infections may also underlie cSCC development in chronically immunosuppressed individuals. Despite their prevalence and disease association, these viruses are not as well studied as the cancer-associated high-risk α-genus HPVs. HPV-associated lesions are characterized by a marked expansion of dividing, basal-like, poorly differentiated viral cells that contain viral genomes. This reflects the ability of HPVs to inhibit epithelial cell differentiation which is likely driven by the need to establish and maintain long-term viral infections in basal-like epithelial cells. Remarkably, the β-HPVs accomplish this by targeting different cellular effectors than the α-genus HPVs. It was previously reported that the HPV8 E6 protein restrains epithelial cell differentiation by inhibiting Notch and TGF-β signaling. Here we report that the HPV8 E6 protein can subvert Hippo signaling by activating TEAD transcriptional programs that inhibit the expression of keratinocyte differentiation markers. Moreover, we determined that HPV8 E6 can interfere with gene expression programs triggered by Wnt signaling by binding to the β-catenin-associated transcriptional co-activator BCL9L and that this also serves to restrain the expression of epithelial differentiation markers. Hence the HPV8 E6 protein has evolved a remarkably large array of mechanisms to subvert the differentiation program of the infected epithelial cells.IMPORTANCEHuman papillomaviruses (HPVs) infect basal epithelial cells and cause a dramatic expansion of basal-like, proliferative cells. This reflects the ability of papillomaviruses to delay keratinocyte differentiation thereby maintaining aspects of the basal cell identity of persistently infected cells. This may enable papillomaviruses to establish and maintain long-term infections in squamous epithelial tissues. Previous work has revealed that the ability of β-HPV8 E6 protein to inhibit NOTCH and TGF-β signaling importantly contributes to this activity. Here we present evidence that HPV8 E6 also subverts Hippo and Wnt signaling and that these activities also aid in restraining keratinocyte differentiation.