bluuebunny/crossref_metadata_2025_split huggingface dataset:
Psychological stress disturbs bone metabolism via miR-335-3p/Fos signaling in osteoclast
Authors: Zhang Jiayao , Li Juan , Huang Jiehong , Xiang Xuerui , Li Ruoyu , Zhai Yun , Lin Shuxian , Liu Weicai 
Published: February 2024

AbstractIt has been well-validated that chronic psychological stress leads to bone loss, but the underlying mechanism remains unclarified. In this study, we established and analyzed the chronic unpredictable mild stress (CUMS) mice to investigate the miRNA-related pathogenic mechanism involved in psychological stress induced osteoporosis. Our result found that these CUMS mice exhibited osteoporosis phenotype that mainly attributed to the abnormal activities of osteoclasts. Subsequently, miRNA sequencing and other analysis showed that miR-335-3p, which is normally highly expressed in the brain, was significantly down-regulated in the nucleus ambiguous (NAC), serum, and bone of the CUMS mice. Additionally,in vitrostudies detected that miR-335-3p is important for osteoclast differentiation, with its direct targeting site in FOS. Further studies demonstrated FOS was upregulated in CUMS osteoclast, and the inhibition of FOS suppressed the accelerated osteoclastic differentiation, as well as the expression of osteoclastic genes, such asNfatc1, Acp5, Mmp9, in miR-335-3p restrained osteoclasts. In conclusion, this work indicated that psychological stress may down-regulate the miR-335-3p expression, which resulted in the accumulation of FOS and the up-regulation of NFACT1 signaling pathway in osteoclasts, leading to its accelerated differentiation and abnormal activity. These results decipher a previously unrecognized paradigm that miRNA can act as a link between psychological stress and bone metabolism.Impact statementmiR-335-3p, which targets FOS and inhibits its activation of NFATC1 signaling, is an important regulator for osteoclast function and responsible for the psychological stress induced osteoporosis
Regulated mRNA recruitment in dinoflagellates is reflected in hyper-variable mRNA spliced leaders and novel eIF4Es
Authors: Jones Grant D. , Williams Ernest P. , Haq Saddef , Bachvaroff Tsvetan R. , Sanchez M. Basanta , Place Allen R. , Jagus Rosemary 
Published: February 2024

AbstractDinoflagellates are eukaryotic algae with large genomes that rely heavily on post-transcriptional control for the regulation of gene expression. Dinoflagellate mRNAs aretrans-spliced with a conserved 22 base spliced leader sequence (SL) that includes the 5’-cap to which the translation initiation factor 4E (eIF4E) binds to facilitate ribosomal recruitment. The binding of an eIF4E to a specific mRNA SL is a potential regulatory point in controlling dinoflagellate gene expression. Here we show that m7G is the 5’-cap base of the 65 bp SL RNA with additional methylations throughout the SL to give a mixture of novel multi-methylated sequences inAmphidinium carterae(CCMP1314). There is also sequence variability in all four bases seen at the first position followed by a variety of polymorphisms. Three novel clades of eIF4E have been shown in dinoflagellates that are distinct from the three metazoan classes of eIF4E. Members of each clade differ significantly from each other, but all bear the distinctive features of a cap-binding protein. Here we show large differences in expression and activity in six of the eight eIF4E family members fromA. carterae. Transcripts of each are expressed throughout the diel cycle, but only eIF4E-1 family members and eIF4E-2a show discernable expression at the level of protein. Recombinant eIF4E-1 family members and eIF4E-3a, but not eIF4E-2a, are able to bind to m7GTP substratesin vitro. Overall, eIF4E-1a emerges with characteristics consistent with the role of a prototypical initiation factor; eIF4E-1a is the most conserved and highly expressed eIF4E family member, has the highest affinity for m7GpppG and m7GpppC by surface plasmon resonance, and is able to complement a yeast strain conditionally deficient in eIF4E. The large number of eIF4E family members along with the sequence and methylation state variability in the mRNA SLs underscore the unique nature of the translational machinery in the dinoflagellate lineage and suggest a wide range of possibilities for differential recruitment of mRNAs to the translation machinery.Impact StatementIn the dinoflagellate,A. carterae, hyper-variable mRNA spliced leaders and novel eIF4Es reflect the reliance of dinoflagellates on variable mRNA recruitment for the regulation of gene expression.
Wider spread of excitatory neuron influence in association cortex than sensory cortex
Authors: Khoury Christine F. , Ferrone Michael , Runyan Caroline A. 
Published: February 2024

AbstractThe basic structure of local cortical circuits, including the composition of cell types, is highly conserved across the cortical processing hierarchy. However, computational roles and the spatial and temporal properties of population activity differ fundamentally in sensory-level and association-level areas. In primary sensory cortex, the timescale of population activity is shorter and pairwise correlations decay more rapidly over distance between neurons, supporting a population code that is suited to encoding rapidly fluctuating sensory stimuli. In association cortex, the timescale of population activity is longer, and pairwise correlations are stronger over wider distances, a code that is suited to holding information in memory and driving behavior. Here, we tested whether these differences in population codes could potentially be explained by intrinsic differences in local network structure. We targeted single excitatory neurons optogenetically, while monitoring the surrounding ongoing population activity in sensory (auditory cortex) and association (posterior parietal cortex) areas in mice. While the temporal impacts of these perturbations were similar across regions, the spatial spread of excitatory influence was wider in association cortex than in sensory cortex. Our findings suggest that differences in recurrent connectivity could contribute to the different properties of population codes in sensory and association cortex, and imply that circuit models of cortical function should be tailored to the properties specific to individual regions.Significance statementCell-type-specific functional interactions and connectivity patterns have largely been studied in sensory cortex. Yet the properties of local network activity differ dramatically across the cortical hierarchy, possibly due to differences in intrinsic connectivity patterns. Here, we compared the functional impacts of individual excitatory neurons on local population activity, finding differences in the spatial spread of excitatory influence across regions. Our findings suggest that the structure of local networks differs across the cortical processing hierarchy, and these differences should be considered in circuit models of processes such as decision-making and working memory.
CDKN1B(p27kip1) enhances drug tolerant persister CTCs by restricting polyploidy following mitotic inhibitors
Authors: Horwitz Elad , Dubash Taronish D. , Szabolcs Annamaria , Wittner Ben S. , Kreuzer Johannes , Morris Robert , Bardia Aditya , Chirn Brian , Wiley Devon , Che Dante , Russel Hunter C. , Herrera Lopez Xcanda Ixchel , Fox Douglas B. , Antmen Ezgi , Ting David T. , Haas Wilhelm , Sade-Feldman Moshe , Maheswaran Shyamala , Haber Daniel A. 
Published: February 2024

ABSTRACTThe mitotic inhibitor docetaxel (DTX) is often used to treat endocrine-refractory metastatic breast cancer, but initial responses are mitigated as patients eventually have disease progression. Using a cohort ofex vivocultures of circulating tumor cells (CTCs) from patients with heavily pretreated breast cancer (n=18), we find two distinct patterns of DTX susceptibility, independent of clinical treatment history. In CTCs cultured from some patients, treatment with a single dose of DTX results in complete cell killing, associated with accumulation of non-viable polyploid (≥8N) cells arising from endomitosis. In others, a transient viable drug-tolerant persister (DTP) population emerges, ultimately enabling renewed proliferation of CTCs with preserved parental cell ploidy and DTX sensitivity. In these CTC cultures, efficient cell cycle exit generates a ≤4N drug-tolerant state dependent onCDKN1B(p27Kip1). Exposure to DTX triggers stabilization of CDKN1B through AKT-mediated phosphorylation at serine 10. Suppression ofCDKN1Breduces the number of persister CTCs, increases ≥8N mitotic cells and abrogates regrowth after DTX exposure. Thus, CDKN1B-mediated suppression of endomitosis contributes to a reversible persister state following mitotic inhibitors in patient-derived treatment refractory breast cancer cells.Summary in bulletsTransient DTX tolerant persister cells emerge in some patient-derived cultured CTCs.DTX-tolerant persisters restrict endoreduplication and polyploidy through CDKN1 (p27kip1).DTX exposure induces CDKN1B stabilization through AKT mediated phosphorylation at serine 10.Suppression of polyploidy underlies a drug tolerant persister state specific to mitotic inhibitors.
RomX, a novel prokaryotic regulator, links the response receiver domain of RomR with GTP-bound MglA for establishingMyxococcus xanthuspolarity
Authors: Chakraborty Sukanya , Gayathri Pananghat 
Published: February 2024

AbstractCell polarity specification and reversals are distinctive features of motility of the soil bacteriumMyxococcus xanthus. The bacterial small Ras-like GTPase, MglA, serves as a key player orchestrating these polarity oscillations. RomR, a response regulator, along with its partner RomX, has been identified to function as a guanine nucleotide exchange factor (GEF) for MglA, crucial for its polar recruitment. In this study, we determine the crystal structure of RomX, a protein of a hitherto unknown fold. RomX consists of a three-helix bundle, identified to be the same fold as the stalk domain of atlastin, a member of the dynamin family of GTPases. From our structure-based sequence analysis for proteins of a similar fold, we observe the co-occurrence of the RomX fold with response receiver domains in several bacterial response regulators. Based on mutational analysis and affinity measurements, we conclude that the helix-1 of RomX mediates the interaction with MglA-GTP, while helix-3 of RomX interacts with the RomR N-terminal receiver (REC) domain. We demonstrate that the binding between MglA and RomX is exclusively in the presence of GTP. The absence of additional stimulation of RomX GEF activity in the presence of RomR-REC supports the mutually exclusive interface on RomX for RomR and MglA interaction. Collectively, our findings validate the positioning of RomX between MglA and RomR-REC, providing insights into the concerted action of the RomR/RomX complex at both poles in driving MglA localization within polarized cells.
Age-dependent miR156-targetedSPLsare required for extrafloral nectary development inPassifloraspp
Authors: Soares Jéssica Ribeiro , Robledo Kerly Jessenia Moncaleano , de Souza Vinicius Carius , Dias Lana Laene Lima , Silva Lázara Aline Simões , da Silveira Emerson Campos , da Silva Souza Claudinei , Sousa Elisandra Silva , Sodrzeieski Pedro Alexandre , Sarmiento Yoan Camilo Guzman , de Matos Elyabe Monteiro , Falcão Thais Castilho de Arruda , Fialho Lilian da Silva , Guimarães Valéria Monteze , Viccini Lyderson Facio , Pierdona Flaviani Gabriela , Romanel Elisson , Fouracre Jim , Otoni Wagner Campos , Nogueira Fabio Tebaldi Silveira 
Published: February 2024

SUMMARY-Passion flower extrafloral nectaries (EFNs) protrude from adult leaves and facilitate mutualistic interactions with insects, but how age cues control EFN establishment remains poorly understood.-Here, we combined genetic and molecular studies to investigate how leaf development and EFN patterning are regulated through the age-dependent miR156-SQUAMOSA PROMOTER BINDING PROTEIN LIKE(SPL) module in two EFN-containingPassifloraspecies with distinct leaf shapes.-Low levels of miR156 correlate with leaf maturation and EFN formation inPassiflora edulis and P. cincinnata. Consistently, overexpression of miR156 (miR156-OE), which leads to low levels ofSPLs, affected leaf ontogeny and EFN development in both species. Laminar EFNs were underdeveloped and less abundant in bothP. edulis and P. cincinnatamiR156-OE leaves. Importantly, the ecological relationships established by EFNs and their sugar profiles were negatively regulated by high levels of miR156. Moreover, transcriptome analysis of young leaf primordia revealed that miR156-targetedSPLsmay be required for proper expression of leaf and EFN development- associated genes inP. edulis and P. cincinnata.-Our work provides the first evidence that the highly conserved miR156/SPLmodule regulates EFN development in an age-dependent manner and that the program responsible for EFN development is closely associated with the heteroblastic developmental program of the EFN-bearing leaves.
Saccharomyces cerevisiaeRev7 promotes non-homologous end-joining by blocking Mre11 nuclease and Rad50’s ATPase activities and homologous recombination
Authors: Badugu Sugith , Dhyani Kshitiza M. , Thakur Manoj , Muniyappa Kalappa 
Published: February 2024

ABSTRACTRecent studies have shown that, in human cancer cells, the tetrameric Shieldin complex (comprising REV7, SHLD1, SHLD2, and SHLD3) facilitates non-homologous end-joining (NHEJ) while blocking homologous recombination (HR). Surprisingly, several eukaryotic species lack SHLD1, SHLD2 and SHLD3 orthologs, suggesting that Rev7 may leverage an alternative mechanism to regulate the double-strand break (DSB) repair pathway choice. Exploring this hypothesis, we discovered thatSaccharomyces cerevisiaeRev7 physically interacts with the Mre11-Rad50-Xrs2 (MRX) subunits, impedes G-quadruplex DNA synergised-HU-induced toxicity and facilitates NHEJ, while antagonizing HR. Notably, we reveal that a 42-amino acid C-terminal fragment of Rev7 binds to the subunits of MRX complex, protectsrev7Δcells from G-quadruplex DNA-HU-induced toxicity, and promotes NHEJ by blocking HR. By comparison, the N-terminal HORMA domain, a conserved protein–protein interaction module, was dispensable. We further show that the full-length Rev7 impedes Mre11 nuclease and Rad50’s ATPase activities without affecting the latter’s ATP-binding ability. Combined, these results provide unanticipated insights into the functional interaction between the MRX subunits and Rev7 and highlight a mechanism by which Rev7 facilitates DSB repair via NHEJ, and attenuation of HR, by blocking Mre11 nuclease and Rad50’s ATPase activities inS. cerevisiae.IMPACT STATEMENTThe mechanisms steering DNA double-strand break repair pathway choice is a topic of intense investigation, but remains incompletely understood. Our findings suggest that yeast Rev7 promotes DSB repair via NHEJ and inhibits homologous recombination by blocking Mre11 nuclease and Rad50’s ATPase activities.
On the Role of VP3-PI3P Interaction in Birnavirus Endosomal Membrane Targeting
Authors: Zanetti Flavia A. , Fernández Ignacio , Baquero Eduard , Guardado-Calvo Pablo , Ferrino-Iriarte Andres , Dubois Sarah , Morel Etienne , Alfonso Victoria , Aguilera Milton O. , Celayes María E. , Polo Luis M. , Suhaiman Laila , Galassi Vanesa V. , Chiarpotti María V. , Allende Carolina , Rodríguez Javier M. , Castón José R. , Lijavetzky Diego , Taboga Oscar , Colombo María I. , Del Pópolo Mario G. , Rey Félix A. , Delgui Laura R. 
Published: February 2024

AbstractBirnaviruses are a group of double-stranded RNA (dsRNA) viruses infecting birds, fish and insects. Early endosomes (EE) constitute the platform for viral replication. Here, we study the mechanism of birnaviral targeting of EE membranes. Using the Infectious Bursal Disease Virus (IBDV) as a model, we validate that the viral protein 3 (VP3) binds to phosphatidylinositol-3-phosphate (PI3P) present in EE membranes. We identify the domain of VP3 involved in PI3P-binding, named P2 and localized in the core of VP3, and establish the critical role of the arginine at position 200 (R200), conserved among all known birnaviruses. Mutating R200abolishes viral replication. Moreover, we propose a two-stage modular mechanism for VP3 association with EE. Firstly, the carboxy-terminal region of VP3 adsorbs on the membrane, and then the VP3 core reinforces the membrane engagement by specifically binding PI3P through its P2 domain, additionally promoting PI3P accumulation.Significance StatementBirnaviruses are a family of viruses unique among the group of dsRNA viruses. Here, we show that VP3 seizes the endosomes by anchoring to the PI3P lipids in the luminal side of the EE membrane, in order to organize the viral replication factory. We propose a two-stage modular mechanism for VP3 association with PI3P-enriched EE. The significance of this work resides in the biochemical and biophysical insights on the mechanism of association of VP3 with EE and its role in the viral life cycle, which represents a substantial contribution toward understanding the replication strategy of these “non-canonical” viruses.
Integrated multi-omics analysis ofKlebsiella pneumoniaerevealed the discrepancy in flavonoid effect against strain growth between Rutin and Luteolin
Authors: Wang Zhibin , Shen Wanxia , Li Yuejiao , Wang Xiaoyun , Xu Guofeng , Yuan Xiefang , Tang Hongmei , Ma Ning , Zhong Xiaolin , Wang Xing 
Published: February 2024

AbstractThe emergence of drug resistant pathogenic bacteria is increasingly challenging conventional antibiotics. Plant derived flavonoids are always considered as potential alternatives to antibiotics due to their antimicrobial properties. However, the molecular mechanisms by which flavonoids inhibit pathogenic microorganisms’ growth are not fully understood. In order to better understand the inhibitory mechanism of flavonoids, two flavonoids were used to incubateKlebsiella pneumoniaeATCC700603. After incubation for 4 hours, both the metabolomic and transcriptomic analysis were performed. In present study, 5,483 genes and 882 metabolites were measured. Compared to wild control, the Rutin and Luteolin induced 507 and 374 differentially expressed genes (DEGs), respectively. However, the number of differential abundant metabolites (DAMs) were the same. The correlation between DEGs and DAMs were studied. The top 10 correlated DEGs and DAMs were identified in each comparative groups. Our results showed that, compared to Luteolin, Rutin induced the accumulation of metabolites and suppressed genes’ expression. Our results provided an explanation for the disparate effects of two flavonoids and demonstrated the inhibitory mechanism of Rutin on strain growth.
The MYCN 5′ UTR as a therapeutic target in neuroblastoma
Authors: Volegova Marina P , Brown Lauren E , Banerjee Ushashi , Dries Ruben , Sharma Bandana , Kennedy Alyssa , Porco John A. , George Rani E 
Published: February 2024

AbstractTumor cell amplification of the MYCN transcription factor is seen in half of patients with high-risk neuroblastoma, where it functions as an oncogenic driver associated with metastatic disease and poor survival. Yet, direct targeting of MYCN has been met with little success, prompting efforts to inhibit its expression at multiple levels. MYCN-amplified neuroblastoma cells have an increased requirement for protein synthesis to meet the overwhelming transcriptional burden imposed by oncogenic MYCN. Here, we take advantage of this vulnerability to interrogate the therapeutic potential of inhibiting the activity of the eukaryotic translation initiation factor 4A1 (eIF4A1), an RNA-helicase responsible for resolving structural barriers such as polypurine preponderance within 5′ untranslated regions (UTRs). We observed that eIF4A1 is a key regulator of transcript-specific mRNA recruitment in MYCN-overexpressing neuroblastomas and MYCN-associated transcripts rank highly in polypurine-rich 5′ UTR sequences, the majority of which have critical roles in cell proliferation. Using CMLD012824, a novel synthetic amidino-rocaglate (ADR) derivative, we demonstrate selectively increased eIF4A1 affinity for polypurine-rich 5′ UTRs, including the MYCN mRNA, leading to translation inhibition and cytotoxicity in human neuroblastoma cell lines and animal models. Through ribosome profiling and PAR-CLIP analysis, we show that ADR-mediated clamping of eIF4A1 onto mRNA spans the full lengths of target transcripts, whereas translational inhibition is mediated selectively through 5′ UTR binding. Both cap-dependent and cap-independent translation of MYCN are disrupted, pointing to the ability of CMLD012824 to disrupt non-canonical translation initiation. Our studies provide insights into the functional role of eIF4A1 in meeting the increased protein synthesis demands of MYCN-amplified neuroblastoma and suggest that its disruption may be therapeutically beneficial in this disease.
Cellular heterogeneity in the developing forebrain masks transcriptional outcomes and principles ofEvf2enhancer lncRNA-Dlx5/6UCE-gene guidance
Authors: Li Edward , Chakraborty Abhijit , Kohtz Sara J. , Cajigas Ivelisse , Shiau Fion , Vassar Robert J. , Clark Brian S. , Kohtz Jhumku D. 
Published: February 2024

AbstractDuring mouse embryonic brain development, theEvf2ultraconserved enhancer (UCE) lncRNA guides the Dlx5/6UCE to ∼129 sites across chr6. However, previous work identified only 4 transcriptionally regulated targets associated withEvf2-Dlx5/6UCE enhancer-gene guided sites (EGGs), raising questions about the significance of the majority ofEvf2-EGGs. Here, single cell transcriptomics (scRNAseq) shows thatEvf2-EGGs on chr6 coincide with subpopulation-specificEvf2transcriptional targets, revealing far greater alignment between EGGs and transcriptional targets than previously reported. Surprisingly, subpopulation-specificEvf2regulated gene networks in embryonic progenitors predict adult synaptic and seizure defects.Evf2regulation of EGGs to gene bodies (GB, Dlx5/6UCE locations within ±5kb of the target gene) divides chr6 into short-range (<10Mb distant), highly activated genes, and long/super-long-range (10-129Mb), moderately repressed genes. Clustering ofEvf2transcriptionally regulated chr6 targets in populations whereEvf2is first activated supports thatEvf2-EGG transcriptional effects can occur from EGG shifts as far as 3Mb, uncoupling enhancer shift distance and transcriptional direction from transcriptional outcome.Evf2RNA binding sites (RBSs) divide chr6 into 4 major regions, consistent with a role for RBS chromosomal spacing in long-and super-long-range EGG selectivity. Surprisingly, 95% of 147 RBSs genome-wide potentially form inter-chromosomal DNA loops.Evf2-regulated combinatorial recruitment ofEvf2-ribonucleoproteins at EGGs and RBSs, together with effects on homeodomain transcription factor DNA motif recognition, support a novel model of lncRNA directed multi-modal EGG selectivity during intra- and inter-chromosomal gene regulation.