bluuebunny/crossref_metadata_2025_split huggingface dataset:
Notch signaling blockade links transcriptome heterogeneity in quiescent neural stem cells with their reactivation routes and potential
Authors: Morizet David , Foucher Isabelle , Alunni Alessandro , Bally-Cuif Laure 
Published: November 2024

AbstractIn the vertebrate brain, neural stem cell (NSC) quiescence is necessary for stemness maintenance. Using single cell RNA sequencing (scRNAseq) in the zebrafish adult telencephalon, we identified different molecular clusters of quiescent NSCs, interpreted to sign different quiescence depths(1). Here, we show that these clusters, when challengedin vivowith an inhibitor of Notch signaling -a major quiescence promoting pathway-, unfold different behaviors. Notably, deeply quiescent NSCs with astrocytic features display a unique activation phenotype that combines the maintenance of astrocytic markers with the rapid upregulation of activation and neuronal commitment genes, reminiscent to murine periventricular astrocytes activating upon lesion. In contrast, an NSC cluster predicted to be in the deepest quiescence state resists Notch blockade, and we demonstrate that the transcription factor Nr2f1b mediates this resistance to activationin vivo. These results together link the molecular heterogeneity of quiescent NSCs withbona fidebiological properties and their molecular regulators.
A geranylgeranyl reductase homolog required for cholesterol production in Myxococcota
Authors: Lee Alysha K. , Welander Paula V. 
Published: November 2024

AbstractMyxococcota is a phylum of sterol producing bacteria. They exhibit a clade depth for sterol biosynthesis unparalleled in the bacterial domain and produce sterols of a biosynthetic complexity that rivals eukaryotes. Additionally, the sterol biosynthesis pathways found in this phylum have been proposed as a potential source for sterol biosynthesis in the last eukaryotic common ancestor, lending an evolutionary importance to our understanding of this pathway in Myxococcota. However, sterol production has only been characterized in a few species and outstanding questions about the evolutionary history of this pathway remain. Here, we identify two myxobacteria,Minicystis roseaandSandaracinus amylolyticus, capable of cholesterol biosynthesis. These two myxobacteria possess a cholesterol biosynthesis pathway that differs in both the ordering and enzymes involved in biosynthesis compared toEnhygromyxa salina, a myxobacterium previously demonstrated to produce cholesterol, as well as the canonical pathways found in eukaryotes. We characterize an alternative bacterial reductase responsible for performing C-24 reduction, further delineating bacterial cholesterol production from eukaryotes. Finally, we examine the distribution and phylogenetic relationships of sterol biosynthesis proteins across both cultured and uncultured Myxococcota species, providing evidence for multiple acquisition events and instances of both horizontal and vertical transfer at the family level. Altogether, this work further demonstrates the capacity of myxobacteria to synthesize eukaryotic sterols but with an underlying diversity in the biochemical reactions which govern sterol synthesis, suggesting a complex evolutionary history and refining our understanding of how myxobacterial cholesterol production relates to their eukaryotic counterparts.Significance StatementSterols are essential and ubiquitous lipids in eukaryotes, but their significance in bacteria is less understood. Sterol production in Myxococcota, a phylum of developmentally complex predatory bacteria, has provided insight into novel sterol biochemistry and prompted discussion regarding the evolution of this pathway within both the eukaryotic and bacterial domains. Here, we characterize cholesterol biosynthesis in two myxobacteria, providing evidence for distinct pathway organization and identifying a unique protein responsible for C-24 reduction. We couple these results to phylogenomic analysis of sterol biosynthesis within Myxococcota revealing a complicated evolutionary history marked by vertical and horizontal transfer, suggesting a mosaic acquisition of this pathway in Myxococcota and highlighting the complex role myxobacteria may have had in sterol transfer to eukaryotes.
New Insights Into The Melanin Structure OfLomentospora prolificans
Authors: Liporagi-Lopes Livia C. , Chrissian Christine , Kacirani Arlind , Camacho Emma , Stark Ruth E. , Casadevall Arturo 
Published: November 2024

AbstractLomentospora prolificansis a filamentous fungus with a global distribution, manifesting particularly higher prevalence in human-impacted environments. This organism is associated with a wide spectrum of human infections, especially in immunosuppressed individuals, for whom it causes severe and debilitating illnesses with high morbidity and mortality that are compounded by its pan-resistant profile with respect to antifungal drugs. Melanin is a ubiquitous pigment among fungi with a broad range of actions that include promoting fungal virulence. Although melanin is one of the most studied virulence factors in pathogenic fungi, relatively little is known about the chemistry of this pigment inL. prolificans.In the current study we characterizedL. prolificans-associated melanin using chemical, biological, biophysical and structural techniques, also assessing the impact of inhibitors of distinct melanization pathways. Our results reveal that this pathogenic fungus makes multiple types of melanin pigments and suggests the possibility of a new type of melanin, which is synthesized together with a mixture of DHN-, DOPA- and pyomelanin types. These insights enhance our understanding ofL. prolificans’virulence mechanisms, paving the way for potential therapeutic interventions.
Suppressor of quenching 1 functions as a methionine sulfoxide reductase in the chloroplast lumen for regulation of photoprotective qH in Arabidopsis
Authors: Hao Jingfang , Johansson Alexander , Svensson Fall Johan , Duan Jianli , Hertle Alexander P. , Brooks Matthew D. , Niyogi Krishna K. , Yoshida Keisuke , Hisabori Toru , Malnoë Alizée 
Published: November 2024

AbstractPhotosynthetic organisms must balance light absorption and energy dissipation to prevent photo-oxidative damage. Non-photochemical quenching (NPQ) dissipates excess light energy as heat, with the quenching component qH providing sustained photoprotection. However, the molecular mechanism underlying qH induction remains unclear. Our study focuses on the thylakoid membrane protein SUPPRESSOR OF QUENCHING 1 (SOQ1) and its inhibition of qH through interaction with LIPOCALIN IN THE PLASTID (LCNP) inArabidopsis thaliana. Structural homology of SOQ1 lumenal domains with bacterial disulfide bond protein D suggested potential thiol-disulfide exchange activity.In vitroassays determined that both SOQ1 thioredoxin-like (Trx-like) and C-terminal (CTD) domains contain a redox-active cysteine pair and evidenced electron transfer from Trx-like to CTD. Importantly, we found that SOQ1 lumenal domains exhibit methionine sulfoxide reductase (Msr) activity converting oxidized methionine residues in LCNP back to methionine, which thereby inactivates LCNP and prevents qH formation. Mutational analyses identified cysteine residues in SOQ1-CTD and methionine residues in LCNP as critical for qH suppression, supporting their role in redox regulation. Additionally, we found that the redox state of SOQ1in vivois light-dependent, shifting from reduced to oxidized under stress conditions, indicating a dynamic regulation of its activity. We conclude that the Trx-like domain of SOQ1 provides reducing power to its CTD displaying Msr activity. SOQ1 is therefore an unusual example of a protein possessing both a disulfide reductase and Msr domain in tandem. Our findings elucidate the redox-regulation mechanism of qH involving SOQ1-mediated methionine reduction of LCNP, providing insights into the intricate control of photoprotective processes in chloroplasts and enhancing our understanding of plant resilience under environmental stress.
ArabidopsisSUFBand CLP protease regulate SUFBC2D to manipulate iron-sulfur cluster biosynthesis in chloroplast
Authors: Cheng Yuting , Liu Zhaoyang , Yang Bing , Jiao Qingsong , Ito Hisashi , Takabayashi Atsushi , Tanaka Ryouichi , Jia Ting , Hu Xueyun 
Published: November 2024

AbstractIron‒sulfur (Fe‒S) clusters are essential cofactors for Fe‒S proteins. SUFBC2D complex is the scaffold responsible for Fe‒S cluster assembly in chloroplasts. However, the regulatory mechanism on SUFBC2D remains elusive. In this study, we report that the transcription ofSUFBresponds rapidly to leaf senescence, whereas the transcription ofSUFCandSUFDdoes not. Intriguingly, their protein contents remain stable during leaf senescence. We further found that leaf death was occurred only whenSUFBRNAi was induced, and SUFB and SUFC contents decreased much faster in theSUFB-RNAi lines than in theSUFC-RNAi lines, indicating that SUFB had a faster turnover rate than SUFC. Moreover, overexpressingSUFBincreased the contents of SUFC and SUFD, and SUFBC2D, whereas overexpressingSUFCdid not increase SUFB and SUFD. Our findings reveal that SUFB stabilizes SUFC and SUFD via forming SUFBC2D, whereas SUFC lacks this function. Furthermore,SUFBexpression was sharply downregulated when the plants were subjected to iron deficiency, whereasSUFCandSUFDexpression was not. Interestingly, the contents of all three SUF members decreased, indicating that plants degrade SUFBC2D in response to iron deficiency by downregulatingSUFBtranscription. We subsequently studied the degradation mechanism of SUFBC2D. Our results indicated that all SUFs are substrates of the caseinolytic protease (CLP) because they all accumulated in the CLP impaired mutant, and they physically interact with CLPS1, the substrate recognition adaptor of CLP. Collectively, our findings provide novel insights into how plants regulate SUFBC2D complex viaSUFBto adapt to leaf senescence and iron deficiency.
DJ-1 deficiency in SH-SY5Y cells reveals dysregulated networks of genes and pathways involved in neuronal function and disease
Authors: Gock Nathan , Kim Grace , Morin Tessa , Mahal Amar , Kostka Julia , Beischlag Timothy V. , Lee Frank J.S. 
Published: November 2024

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease, affecting between 2 – 3% of the population aged 65 and older. Although the etiology of idiopathic PD is still to be elucidated, the study of heritable forms of the disease can provide new understanding into disease mechanisms. Recessively inherited loss of function mutations in thePARK7/DJ-1gene has been found to be causative for familial, early-onset PD. Importantly,PARK7/DJ-1related forms of familial PD replicate common disease phenotypes seen in idiopathic PD, including degeneration of substantia nigra dopaminergic neurons, and Parkinsonism. In this study, we evaluate the loss of function ofPARK7/DJ-1on a human neuronal cell line, SH-SY5Y. Following ablation of thePARK7/DJ-1gene via CRISPR-Cas9, RNA sequencing and the DESEQ2 tool kit were utilized to filter differentially expressed genes betweenPARK7/DJ-1knockouts and control SH- SY5Y cells. 5684 genes were identified to be significantly differentially expressed. 3 genes from each of the top 10 upregulated (ATOH8, LAYN, TLX2) and downregulated (CACNA1B, CPLX2, SV2C) gene lists were selected and confirmed via RT-PCR. Differentially expressed gene lists were run through the WebGestalt functional enrichment analysis toolkit to identify enriched gene ontology (GO) terms for biological processes, cellular components, molecular function, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways respectively. Among the top 10 significantly enriched KEGG pathways for upregulated genes were those related to neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease (p-adj ≤ 0.05). Differentially expressed genes were run through the STRING database to predict protein-protein interactions (PPI). A highly significant PPI enrichment was observed (p < 1.0e-16). Our results indicate that loss of DJ-1 function in human neuronal cells leads to dysregulation of networks of connected genes and pathways that are implicated in neurodegenerative disease as well as neuronal function.
Inhibitors of lysinoalanine crosslinking in the flagella hook as antimicrobials against spirochetes
Authors: Lynch Michael J. , Kurniyati Kurni , Deshpande Maithili , Charon Nyles W. , Li Chunhao , Crane Brian R. 
Published: November 2024

AbstractSpirochetes are especially invasive bacteria that are responsible for several human diseases, including Lyme disease, periodontal disease, syphilis and leptospirosis. Spirochetes rely on an unusual form of motility based on periplasmic flagella (PFs) to infect hosts and evade the immune system. The flexible hook of these PFs contains a post-translational modification in the form of a lysinoalanine (Lal) crosslink between adjacent subunits of FlgE, which primarily comprise the hook. Lal crosslinking has since been found in key species across phylum and involves residues that are highly conserved. The requirement of the Lal crosslink for motility of the pathogensTreponema denticola(Td) andBorreliella burgdorferi(Bb) establish Lal as a potential therapeutic target for the development of anti-microbials. Herein, we present the design, development and application of a NanoLuc-based high-throughput screen that was used to successfully identify two, structurally related Lal crosslink inhibitors (hexachlorophene and triclosan) from a library of clinically approved small molecules. A structure-activity relationship study further expanded the inhibitor set to a third compound (dichlorophene) and each inhibitor was demonstrated to biochemically block autocatalytic crosslinking of FlgE from several pathogenic spirochetes with varied mechanisms and degrees of specificity. The most potent inhibitor, hexachlorophene, alters Lal crosslinking in cultured cells of Td and reduces bacterial motility in swimming plate assays. Overall, these results provide a proof-of-concept for the discovery and development of Lal-crosslink inhibitors to combat spirochete-derived illnesses.
Isoprene deters insect herbivory by priming plant hormone responses
Authors: Sahu Abira , Mostofa Mohammad Golam , Xu Yuan , Serda Bianca M. , Keefe James O’ , Sharkey Thomas D. 
Published: November 2024

AbstractIsoprene, emitted by some plants, enhances plant abiotic resilience but its role in biotic stress resilience remains elusive. We used tobacco plants engineered to emit isoprene (IE) and the corresponding azygous non-emitting control (NE) to investigate isoprene emission and biotic stress resilience. IE plants were more resistant to insect herbivory than NE plants. Worms preferred to feed on NE rather than IE leaves. IE plants showed less decline in photosynthesis during worm feeding. Insect feeding increased jasmonate levels in IE leaves, suggesting isoprene-mediated priming of the jasmonic acid response. Wound-induced increase in isoprene emission corresponded with elevation of methyl-D-erythritol-4-phosphate pathway and Calvin-Benson cycle metabolites. The results highlight interactive functions of isoprene and jasmonic acid and advance our understanding of how isoprene emission enhances plant resilience.
Tcf4Deficiency Causes Recurrent Seizures in Mice
Authors: Craciun Laura , DeNittis Vivianna R. , Davis Matthew T. , Paz Jeanne T. , Saijo Kaoru 
Published: November 2024

ABSTRACTTranscription factor 4 (TCF4) is a transcription factor that is critical for the normal development and function of the central nervous system. Haploinsufficiency ofTCF4causes Pitt-Hopkins Syndrome (PTHS), a lifelong neurodevelopmental disorder characterized by seizures and intellectual disability. To expand our currently limited understanding of TCF4 function and PTHS pathophysiology, we created a mouse model of PTHS with largely astrocyte-specific heterozygous knockout ofTcf4. These mice developed severe recurrent seizures and had decreased lifespans. In addition, we found that these mice had astrogliosis as well as increased neuronal activity in the cortex, hippocampus, amygdala, and hypothalamus. Furthermore, single nucleus RNA sequencing analysis revealed global changes in the gene expression profiles of excitatory neurons, inhibitory neurons, astrocytes, and oligodendrocytes of PTHS compared to wild-type mice. Overall, this is the first report of a PTHS mouse model with seizures, providing the field with a tool to investigate the mechanisms of PTHS development and progression and develop therapeutics for PTHS and its associated epilepsy.HIGHLIGHTSNovel PTHS mouse model that targets astrocytes develops epilepsyPTHS mice exhibit astrogliosis and increased neuron activityChanges in gene expression profile observed in PTHS mice across neurons and glial cells
Intraductal infection with H5N1 clade 2.3.4.4b influenza virus
Authors: Roubidoux Ericka Kirkpatrick , Meliopoulos Victoria , Livingston Brandi , Brigleb Pamela H. , Schultz-Cherry Stacey 
Published: November 2024

AbstractThe ongoing outbreak of highly pathogenic avian influenza (HPAI) H5N1 of the clade 2.3.4.4b in dairy cows has led to numerous questions including how the virus transmits amongst cattle given the limited respiratory infection. One hypothesis is that the virus is spreading through fomites from udder to udder. In these studies, we demonstrate that intraductal inoculation of H5N1 but not H1N1 influenza virus results in infection in mice. This model will be useful to our understanding of the impact of influenza virus on the mammary gland, the potential as a new route of transmission, and can be used to assess if antiviral treatments prevent infections in the mammary gland.
Heart tube morphogenesis is regulated by segment-specific gene regulatory networks controlled by MEF2C
Authors: Muncie-Vasic Jonathon M. , Sinha Tanvi , Clark Alexander P. , Brower Emily F. , Saucerman Jeffrey J. , Black Brian L. , Bruneau Benoit G. 
Published: November 2024

ABSTRACTThe transcription factor MEF2C plays a critical role in the development of the linear heart tube, but the specific transcriptional networks controlled by MEF2C remain largely undefined. To address this, we performed combined single-nucleus RNA-and ATAC-sequencing on wild type and MEF2C-null embryos at distinct stages of development. We identified a broadly “posteriorized” cardiac gene signature and chromatin landscape throughout the heart tube in the absence of MEF2C. By integrating our gene expression and chromatin accessibility data in a deep-learning based model, we were able to construct developmental trajectories for each of the outflow tract, ventricular, and inflow tract lineages and determined how each of these segment-specific trajectories were distinctly altered in the MEF2C-null embryos. We computationally identified potential segment-specific MEF2C-dependent enhancers, and from these candidates, identified novel enhancers with activity in the developing heart tube using transgenesis in zebrafish. Finally, using inferred gene regulatory networks we discovered a genetic interaction betweenMef2cand the atrial nuclear hormone receptorNr2f2, revealing that the MEF2C-null heart malformations are partly driven by a transcriptional network with increased NR2F2 activity. These studies not only provide a rich description of the genomic regulation of early heart tube development, but provide a generalizable framework for using genetic mutants to dissect the transcriptional networks that govern developmental processes.
Network-based representation learning reveals the impact of time and diet on the gut microbial and metabolomic environment of infants
Authors: Price Adelle , Rasolofomanana-Rajery Sakaiza , Manpearl Keenan , Robertson Charles E. , Krebs Nancy F. , Frank Daniel N. , Hendricks Audrey E. , Krishnan Arjun , Tang Minghua 
Published: November 2024

AbstractWhile studies have explored differences in gut microbiome development regarding infant liquid diets (breastmilk, formula), surprisingly little is known about the impact of complementary foods on the infant gut microbiome. Indeed, current dietary recommendations for infants and toddlers are not formulated with knowledge of how the developing gut microbiome metabolizes complementary foods. Here, we investigated how different protein-rich foods (i.e., meat vs. dairy) affect fecal metagenomics and metabolomics during early complementary feeding from 5-12 months in formula-fed infants. We used a network node embedding to model the time-dependent, complex interactions between microbiome features, metabolomic compound features, and diet. We then used the embedded space to detect features associated with baseline or endpoint and meat or dairy diet-finding enriched networks of microbiome and metabolomic features, and compared the results to those found using a more traditional differential abundance analysis.
CandidaSpecies Isolated in Female Patients of Reproductive Age with Vaginal Candidiasis in Gualeguaychú, Entre Ríos, Argentina
Authors: Iván Rodrigo Pérez Duarte , Georgina Razetto , Érica Leiva Silvina , Luciano Torres , Josefina Juárez María 
Published: November 2024

AbstractObjective: To identify theCandidaspecies isolated in female patients of reproductive age with vaginal candidiasis. To determine the antifungal (ATF) sensitivity profile of the isolatedCandidaspecies.Materials and methods: Cross-sectional descriptive study, in which 124Candida sppstrains from vaginal discharge samples were isolated in Sabouraud medium supplemented with glucose.CHRO Magar Candidawas used for species identification and complementary tests such as germ tube, chlamydoconidia development and investigation of trehalose assimilation were performed.In vitrosensitivity was investigated by diffusion method with ATF discs fluconazole (FLU), itraconazole (ITRA) and amphotericin B (AMB).Results: C. albicanswas observed in 85.5% of the isolates followed byC. glabratawith 7.3%,C. krusei4%,C. tropicalis2.4% and otherCandidaspecies. For FLU, 0.9% ofC. albicans, 11.1% ofC. glabrataand 100% ofC. kruseiisolates showed resistance. For ITRA, 17% ofC. albicansisolates, 55.6% ofC. glabrataand 100% ofC. kruseiwere resistant. There were no isolates resistant to AMB.Conclusions: Vaginal candidiasis continues to presentCandida albicansas the main etiological agent, which is widely sensitive to ATFs.C. glabrataandC. kruseispecies show increased resistance to azoles. The results obtained ratify the growing need forCandidaspecies identification tests and determination ofin vitrosensitivity to ATFs in order to guide the treatment of vaginal candidiasis towards therapeutic success.