bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis
Authors: Shelton Spencer D. , House Sara , Ramesh Vijayashree , Chen Zhenkang , Wei Tao , Wang Xun , Llamas Claire B. , Venigalla Siva Sai Krishna , Menezes Cameron J. , Zhao Zhiyu , Gill Jennifer G. , DeBerardinis Ralph J. , Morrison Sean J. , Tasdogan Alpaslan , Mishra Prashant 
Published: September 2023

AbstractMitochondrial DNA (mtDNA) mutations are frequently observed in cancer, but their contribution to tumor progression is controversial. To evaluate the impact of mtDNA variants on tumor growth and metastasis, we created human melanoma cytoplasmic hybrid (cybrid) cell lines transplanted with wildtype mtDNA or pathogenic mtDNA encoding variants that partially or completely inhibit oxidative phosphorylation. Homoplasmic pathogenic mtDNA cybrids reliably established tumors despite dysfunctional oxidative phosphorylation. However, pathogenic mtDNA variants disrupted spontaneous metastasis of subcutaneous tumors and decreased the abundance of circulating melanoma cells in the blood. Pathogenic mtDNA did not induce anoikis or inhibit organ colonization of melanoma cells following intravenous injections. Instead, migration and invasion were reduced, indicating that limited circulation entry functions as a metastatic bottleneck amidst mtDNA dysfunction. Furthermore, analysis of selective pressure exerted on the mitochondrial genomes of heteroplasmic cybrid lines revealed a suppression of pathogenic mtDNA allelic frequency during melanoma growth. Collectively, these findings demonstrate that functional mtDNA is favored during melanoma growth and enables metastatic entry into the blood.
Bone Morphogenetic Protein (BMP) signaling upregulates expression of ID1 and ID3 in pancreatitis and pancreatic ductal adenocarcinoma
Authors: Raghunathan Megha , Scully Kathleen M. , Wehrmaker Amanda , Murad Rabi , Lowy Andrew M. , Maurer H. Carlo , DelGiorno Kathleen E. , Itkin-Ansari Pamela 
Published: September 2023

AbstractIdentification of biological modulators of pancreatic ductal adenocarcinoma (PDAC) initiation and progression is of critical importance as it remains one of the deadliest cancers. We have previously shown that ID1 and ID3 are highly expressed in human PDAC and function to repress expression of E47 target genes involved in acinar cell differentiation and quiescence. Here, mining of large bulk RNA-seq and single cell RNA-seq (scRNA-seq) datasets has associated high expression of ID1 and ID3 with poor PDAC patient survival. We show that upregulated expression of ID1 and ID3 in human PDAC cells occurs in response to canonical BMP signaling through pSMAD1/5/9. Conversely, treatment with Noggin, an endogenous BMP antagonist, or with DMH1 and LDN193189, small molecule inhibitors of BMP receptors, reduced expression of ID1, ID3 and cell cycle control genes. Based on our RNA-seq and immunohistochemical analyses, upregulation of BMP signaling to ID1 and ID3 is an early event that occurs in human pancreatic intraepithelial neoplasia (PanIN) and murine models of pre-neoplastic lesions induced by mutant Kras. Strikingly, the same result was observed in a murine model of pancreatitis induced by the cholecystokinin (CCK) analog caerulein. Moreover, we show that caerulein is sufficient to induce BMP signaling and expression of ID1 and ID3 in a cell-autonomous manner in non-transformed rodent exocrine pancreas cells. Together, the data suggest that canonical BMP signaling upregulates expression of ID1 and ID3 early in pancreas pathogenesis and that pancreatic cancer cells remain addicted to this important signaling circuit as the disease progresses. Future exploration of druggable targets within this pathway could be of therapeutic benefit in the treatment of pancreatitis and PDAC.
Replication protein-A, RPA, plays a pivotal role in the maintenance of recombination checkpoint in yeast meiosis
Authors: Sampathkumar Arivarasan , Chen Zhong , Tang Yuting , Fujita Yurika , Ito Masaru , Shinohara Akira 
Published: September 2023

SummaryDNA double-strand breaks (DSBs) activate DNA damage responses (DDR) in both mitotic and meiotic cells. A single-stranded DNA (ssDNA) binding protein, Replication protein-A (RPA) binds to the ssDNA formed at DSBs to activate ATR/Mec1 kinase for the response. Meiotic DSBs induce homologous recombination monitored by a meiotic DDR called the recombination checkpoint that blocks the pachytene exit in meiotic prophase I. In this study, we showed the essential role of RPA in the maintenance of the recombination checkpoint duringS. cerevisiaemeiosis. The depletion of an RPA subunit, Rfa1, in a recombination-defectivedmc1mutant, fully alleviates the pachytene arrest with the persistent unrepaired DSBs. RPA depletion decreases the activity of a meiosis-specific CHK2 homolog, Mek1 kinase, which in turn activates the Ndt80 transcriptional regulator for pachytene exit. These support the idea that RPA is a sensor of ssDNAs for the activation of meiotic DDR. Rfa1 depletion also accelerates the prophase I delay in thezip1mutant defective in both chromosome synapsis and the recombination, suggesting that the accumulation of ssDNAs rather than defective synapsis triggers prophase I delay in thezip1mutant.
Trapping non-cognate nucleotide upon initial binding for replication fidelity control in SARS-CoV-2 RNA dependent RNA polymerase
Authors: Romero Moises E. , McElhenney Shannon J. , Yu Jin 
Published: September 2023

AbstractThe RNA dependent RNA polymerase (RdRp) in SARS-CoV-2 is a highly conserved enzyme responsible for viral genome replication/transcription. Here we investigate computationally natural non-cognate vs cognate nucleotide addition cycle (NAC) and intrinsic nucleotide selectivity during the viral RdRp elongation, focusingprechemicallyfrom initial nucleotide substrate binding (enzyme active site open) to insertion (active site closed) of RdRp in contrast with one-step only substrate binding process. Current studies have been first carried out using microsecond ensemble equilibrium all-atom molecular dynamics (MD) simulations. Due to slow conformational changes (from the open to closed) accompanying nucleotide insertion and selection, enhanced or umbrella sampling methods have been further employed to calculate free energy profiles of the non-cognate NTP insertion. Our studies show notable stability of noncognate dATP and GTP upon initial binding in the active-site open state. The results indicate that while natural cognate ATP and Remdesivir drug analogue (RDV-TP) are biased to be stabilized in the closed or insertion state, the natural non-cognate dATP and GTP can be well trapped inoff-pathinitial binding configurations. Current work thus presents an intrinsic nucleotide selectivity mechanism of SARS-CoV-2 RdRp for natural substrate fidelity control in viral genome replication.
Heterogeneity and genomic evolution of metastatic prostate cancer
Authors: Wu Sijia , Lu Zhennan , Wang Yanfei , Zhou Xiaobo , Huang Liyu 
Published: September 2023

AbstractBackgroundMetastasis is the primary cause of prostate cancer-related deaths. However, the underlying molecular mechanisms and evolutionary patterns remain largely uncharacterized.MethodsWe evaluate the heterogeneity and genomic evolution of prostate cancer with multi-organ metastases. The samples include 32 primary samples, 23 lymph node metastases, 22 bone metastases, 16 liver metastases, and four pelvic mess metastases. They are analyzed to identify the mutated genes enriched in metastatic samples, selected by metastases, and leading to different long-distance migrations. These metastasis-related alterations constitute a Mscore for evaluating the metastatic risk of primary prostate tumors.ResultsOur analysis discovers 21 metastasis-related mutated genes in total. Of them, 14 genes are finally selected for metastatic risk prognosis, including the mutations ofARandKMT2Cwith high prediction ability. A Mscore established with these 14 characteristics by the xgboost model displays its ability to classify primary tumors and metastases. This score can further divide primary prostate tumors from the TCGA cohort into two groups. The two subsets present significantly differential survival risks. This score can also identify metastasis-featured primary tumors for breast cancer, bladder cancer, liver cancer, and uterine corpus endometrial carcinoma.ConclusionOur research proposes 14 molecular features potentially driving prostate cancer metastasis. The Mscore established on them can estimate the metastatic risk of primary tumors.
Neutralization of SARS-CoV-2 EG.5/EG.5.1 by sera from ZF2001 RBD-dimer and its next-generation vaccines
Authors: An Yaling , Zhou Xuemei , Tao Lifeng , Xie Haitang , Yang Chenxi , Li Dedong , Wang Ruyue , Hu Hua , Liu Kefang , Dai Lianpan , Xu Kun , Gao George F. 
Published: September 2023

AbstractSARS-CoV-2 Omicron EG.5 and EG.5.1 are surging in several areas of the world, including China. Compared with XBB.1, EG.5 contains additional mutations of F456L and S486P in the spike protein receptor binding domain (RBD) and its subvariant EG.5.1 carries a further spike mutation Q52H. The immune escape potential of EG.5/EG.5.1 is of great concern. In this study, we evaluated the neutralization activities of sera from participants who received COVID-19 inactivated vaccines, protein subunit vaccine ZF2001 or a booster vaccination of Delta-BA.5 RBD-heterodimer protein vaccine, and participants who had a breakthrough infection during a wave of BF.7/BA.5.2 circulation in December 2022. Neutralization profiles elicited by bivalent RBD-heterodimer vaccine candidates containing XBB.1.5 antigen were evaluated in a murine model. We found that EG.5 and EG.5.1 displayed similar immune evasion potential to XBB.1 and XBB.1.5. The Delta-BA.5 RBD-heterodimer booster induced higher neutralizing titers against the tested XBB subvariants, including EG.5 and EG.5.1, than breakthrough infection by BF.7 or BA.5.2. In addition, Delta-XBB.1.5 and BQ.1.1-XBB.1.5 RBD-heterodimer vaccines induced high neutralizing activities against XBB sub-variants in a murine model, suggesting that next-generation COVID-19 vaccines with updated components must be developed to enhance the protection efficacy against the circulating SARS-CoV-2 strains.
Baloxavir marboxil use for critical human infection of avian influenza A H5N6 virus
Authors: Guan Wenda , Qu Rong , Shen Lihan , Mai Kailin , Pan Weiqi , Lin Zhengshi , Chen Liping , Dong Ji , Zhang Jiawei , Feng Pei , Weng Yunceng , Yu Minfei , Guan Peikun , Zhou Jinchao , Tu Chuanmeizi , Wu Xiao , Wang Yang , Yang Chunguang , Ling Yun , Le Sheng , Zhan Yangqing , Li Yimin , Liu Xiaoqing , Zou Heyan , Huang Ziqi , Zhou Hongxia , Wu Qiubao , Zhang Wenjie , He Jiayang , Xu Teng , Zhong Nanshan , Yang Zifeng 
Published: September 2023

AbstractBackgroundRecent increase in human infections of highly pathogenic avian influenza H5N6 virus and its high mortality have raised concerns.MethodsTo analyze evolution of outcomes, longitudinal clinical data and specimens were collected from five patients infected with H5N6 virus after admission. All patients received antiviral treatment either sequentially or in combination of oseltamivir with baloxavir. Severity of illness, and viral load in sputum, urine and blood, and cytokine levels in serum and sputum were serially analyzed.ResultsWhen delayed oseltamivir showed poor effects on high respiratory viral load, baloxavir was prescribed and viral load had a rapid reduction. All patients developed acute respiratory distress syndrome (ARDS) and sepsis within one week after disease onset, three patients died eventually. Nonsurvivors had more severe preexisting condition, extrapulmonary organ dysfunction and insufficient H5N6 virus-specific antibody response. Grouped by delta SOFA on the sample collection date, serum levels of IL-1α, IL-1β, IL-1RA, MIF, Mig, MIP-1α, IFN-γ, IL-12p40, IL-16, IL-18, IL-2Rα, IL-6, basic FGF, G-CSF, HGF, M-CSF, SCF were identified as indicator cytokines reflecting sepsis progression; and sputum levels of IL-18, IL-6, HGF, M-CSF were indicators of ARDS progression. Comparisons of cytokine levels before, during and after baloxavir treatment suggested that, baloxavir may also reduce a few indicator cytokines in sputum and serum that related to viral load and multi-organ dysfunction.ConclusionsBaloxavir can effectively reduce viral load and few proinflammatory cytokines associated with deterioration. However, disease outcome is determined by severity of preexisting conditions and multi-organ dysfunction.Highlights(1)Baloxavir potently decreased viral load in avian influenza H5N6 human infections.(2)Preexisting conditions, extrapulmonary dysfunction and systemic inflammation determined prognosis of H5N6 patients.(3)Indicator cytokines in sputum and serum reflecting ARDS and sepsis progression respectively, were identified in H5N6 patients.
Comparative pangenomic insights into the distinct evolution of virulence factors among grapevine trunk pathogens
Authors: Garcia Jadran F. , Morales-Cruz Abraham , Cochetel Noé , Minio Andrea , Figueroa-Balderas Rosa , Rolshausen Philippe E. , Baumgartner Kendra , Cantu Dario 
Published: September 2023

AbstractThe permanent organs of grapevines (V. viniferaL.), like other woody perennials, are colonized by various unrelated pathogenic ascomycete fungi secreting cell wall-degrading enzymes and phytotoxic secondary metabolites that contribute to host damage and disease symptoms. Trunk pathogens differ in the symptoms they induce and the extent and speed of damage. Isolates of the same species often display a wide virulence range, even within the same vineyard. This study focuses onEutypa lata,Neofusicoccum parvum, andPhaeoacremonium minimum, causal agents of Eutypa dieback, Botryosphaeria dieback, and Esca, respectively. We sequenced fifty isolates from viticulture regions worldwide and built nucleotide-level, reference-free pangenomes for each species. Through examining genomic diversity and pangenome structure, we analyzed intraspecific conservation and variability of putative virulence factors, focusing on functions under positive selection, and recent gene-family dynamics of contraction and expansion. Our findings reveal contrasting distributions of putative virulence factors in the core, dispensable, and private genomes of each pangenome. For example, CAZymes were prevalent in the core genomes of each pangenome, whereas biosynthetic gene clusters were prevalent in the dispensable genomes ofE. lataandP. minimum. The dispensable fractions were also enriched in Gypsy transposable elements and virulence factors under positive selection (polyketide synthases genes inE. lataandP. minimumglycosyltransferases inN. parvum). Our findings underscore the complexity of the genomic architecture in each species and provide insights into their adaptive strategies, enhancing our understanding of the underlying mechanisms of virulence.
STING activation counters glioblastoma by vascular alteration and immune surveillance
Authors: Joseph Justin V. , Blaavand Mathilde S. , Cai Huiqiang , Vernejoul Fabienne , Knopper Rasmus W. , Lindhardt Thomas B. , Skipper Kristian A. , Axelgaard Esben , Reinert Line , Mikkelsen Jacob G. , Borghammer Per , Degn Søren E. , Perouzel Eric , Hager Henrik , Hansen Brian , Kalucka Joanna M. , Vendelbo Mikkel , Paludan Søren R. , Thomsen Martin K. 
Published: September 2023

AbstractGlioblastoma (GBM) is an aggressive brain tumor with a median survival of 15 months and has limited treatment options. Immunotherapy with checkpoint inhibitors has shown minimal efficacy in combating GBM, and large clinical trials have failed. New immunotherapy approaches and a deeper understanding of immune surveillance of GBM are needed to advance treatment options for this devastating disease. In this study, we used two preclinical models of GBM: orthotopically delivering either GBM stem cells or employing CRISPR-mediated tumorigenesis by adeno-associated virus, to establish immunologically proficient and non-inflamed tumors, respectively. After tumor development, the innate immune system was activated through long-term STING activation by a pharmacological agonist, which reduced tumor progression and prolonged survival. Recruitment and activation of cytotoxic T-cells were detected in the tumors, and T-cell specificity towards the cancer cells was observed. Interestingly, prolonged STING activation altered the tumor vasculature, inducing hypoxia and activation of VEGFR, as measured by a kinome array and VEGF expression. Combination treatment with anti-PD1 did not provide a synergistic effect, indicating that STING activation alone is sufficient to activate immune surveillance and hinder tumor development through vascular disruption. These results guide future studies to refine innate immune activation as a treatment approach for GBM, in combination with anti-VEGF to impede tumor progression and induce an immunological response against the tumor.
The protein phosphatase-2A subunit PR130 is linked to cytotoxic protein aggregate formation in mesenchymal pancreatic ductal adenocarcinoma cells
Authors: Nguyen Alexandra , Leydecker Alessa K. , Mustafa Al-Hassan M. , Murr Janine , Butter Falk , Krämer Oliver H. 
Published: September 2023

ABSTRACTProtein phosphatase-2A (PP2A) is a major source of cellular serine/threonine phosphatase activity. PP2A B-type subunits regulate the intracellular localization and the catalytic activity of PP2A-A/PP2A-C complexes towards individual proteins. There is limited knowledge on how PP2A B-type subunits regulate biologically important functions and if these subunits determine the growth and drug responsiveness of tumor cells. Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with poor prognosis. Mesenchymal PDAC subtypes are more aggressive and metastasis-prone than epithelial subtypes. We show that mesenchymal PDAC cells express significantly higher levels of the PP2A B-type subunit PR130 and its mRNAPpp2r3athan epithelial PDAC cells (n=38). Among 17 PP2A B-type subunits, this differential regulation is unique forPpp2r3aand PR130. The higher levels of PR130 in mesenchymal PDAC cells are linked to their vulnerability to the PP2A inhibitor phendione. Phendione induces apoptosis and an accumulation of cytotoxic protein aggregates in such cells. These processes occur independently of the major tumor suppressor p53, which is frequently mutated in PDAC cells. Proteomic analyses reveal that phendione upregulates the chaperone heat shock protein HSP70 in mesenchymal PDAC cells. Inhibition of HSP70 promotes phendione-induced apoptosis. We additionally disclose that phendione promotes a proteasomal degradation of PR130. Genetic elimination of PR130 sensitizes mesenchymal PDAC cells to phendione-induced apoptosis and protein aggregate formation. These data illustrate pharmacologically amenable, selective dependencies of mesenchymal PDAC cells on PP2A-PR130 and HSP70. PP2A inhibition triggers a harmful accumulation of protein aggregates in neurons. This undesired mechanism might be exploited to kill mesenchymal tumor cells.Abstract FigureHIGHLIGHTS➢ The PP2A subunit PR130 is a molecular marker of mesenchymal PDAC cells➢ The small molecule PP2A inhibitor phendione selectively kills mesenchymal PDAC cells➢ Phendione decreases PR130 through proteasomes and selectively increases the heat shock protein 70 kDa in mesenchymal PDAC cells➢ HSP70 promotes cell survival upon inhibition of PP2A➢ PP2A-PR130 regulates the accumulation of cytotoxic protein aggregates in mesenchymal PDAC cells
Rho of plant GTPases with geranylgeranylation motif modulate monoterpene indole alkaloid biosynthesis inCatharanthus roseus
Authors: Bomzan Dikki Pedenla , Sharma Anuj , Cruz Pamela Lemos , Carqueijeiro Ines , Bellenger Léo , Rai Avanish , Thippesh Akshay Kumar , Venkatesha S.C. , Parihar Durgesh , Ducos Eric , Courdavault Vincent , Nagegowda Dinesh A. 
Published: September 2023

ABSTRACTRho Of Plant (ROP) GTPases function as molecular switches that control signaling processes essential for growth, development, and defense. However, their role in specialized metabolism is poorly understood. Previously, we demonstrated that inhibition of protein geranylgeranyl transferase (PGGT-I) negatively impacts the biosynthesis of monoterpenoid indole alkaloids (MIA) inCatharanthus roseus, indicating the involvement of prenylated proteins in signaling. Here, we show through biochemical, molecular andin plantaapproaches that specific geranylgeranylated ROPs modulateC. roseusMIA biosynthesis. Among the sixC. roseusROP GTPases (CrROPs), only CrROP3 and CrROP5, having a C- terminal CSIL motif, were specifically prenylated by PGGT-I. Additionally, both of their transcripts showed higher expression in most parts compared to otherCrROPs. Protein- protein interaction studies revealed that both CrROP3 and CrROP5, but not CrROP2 (lacking CSIL motif), interacted with CrPGGT-I. Further, CrROP3 and CrROP5 exhibited nuclear localization, whereas CrROP2 was localized to plasma membrane.In plantafunctional studies revealed that silencing ofCrROP3andCrROP5negatively affected MIA biosynthesis, while their overexpression upregulated MIA formation. In contrast, silencing and overexpression ofCrROP2had no effect on MIA biosynthesis. Moreover, overexpression of ΔCrROP3and ΔCrROP5mutants lacking the CSIL motif failed to enhance MIA biosynthesis. Taken together, these results implicate that CrROP3 and CrROP5 have positive regulatory role on MIA biosynthesis and thus shed light on how geranylgeranylated ROP GTPases mediate the modulation of specialized metabolism inC. roseus.
Bacteria conjugate ubiquitin-like proteins to interfere with phage assembly
Authors: Hör Jens , Wolf Sharon G. , Sorek Rotem 
Published: September 2023

AbstractMultiple immune pathways in humans conjugate ubiquitin-like proteins to virus and host molecules as a means of antiviral defense. Here we studied an anti-phage defense system in bacteria, comprising a ubiquitin-like protein, ubiquitin-conjugating enzymes E1 and E2, and a deubiquitinase. We show that during phage infection, this system specifically conjugates the ubiquitin-like protein to the phage central tail fiber, a protein at the tip of the tail that is essential for tail assembly as well as for recognition of the target host receptor. Following infection, cells encoding this defense system release a mixture of partially assembled, tailless phage particles, and fully assembled phages in which the central tail fiber is obstructed by the covalently attached ubiquitin-like protein. These phages exhibit severely impaired infectivity, explaining how the defense system protects the bacterial population from the spread of phage infection. Our findings demonstrate that conjugation of ubiquitin-like proteins is an antiviral strategy conserved across the tree of life.