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scifact_entailment

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[ "The wobble modification in tRNAs, 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U), is required for the proper decoding of NNR codons in eukaryotes.", "The 2-thio group confers conformational rigidity of mcm(5)s(2)U by largely fixing the C3'-endo ribose puckering, ensuring stable and accurate codon-anticodon pairing.", "We have identified five genes in Saccharomyces cerevisiae, YIL008w (URM1), YHR111w (UBA4), YOR251c (TUM1), YNL119w (NCS2) and YGL211w (NCS6), that are required for 2-thiolation of mcm(5)s(2)U. An in vitro sulfur transfer experiment revealed that Tum1p stimulated the cysteine desulfurase of Nfs1p, and accepted persulfide sulfurs from Nfs1p.", "URM1 is a ubiquitin-related modifier, and UBA4 is an E1-like enzyme involved in protein urmylation.", "The carboxy-terminus of Urm1p was activated as an acyl-adenylate (-COAMP), then thiocarboxylated (-COSH) by Uba4p.", "The activated thiocarboxylate can be utilized in the subsequent reactions for 2-thiouridine formation, mediated by Ncs2p/Ncs6p.", "We could successfully reconstitute the 2-thiouridine formation in vitro using recombinant proteins.", "This study revealed that 2-thiouridine formation shares a pathway and chemical reactions with protein urmylation.", "The sulfur-flow of eukaryotic 2-thiouridine formation is distinct mechanism from the bacterial sulfur-relay system which is based on the persulfide chemistry." ]

[ 0 ]

[ "Fever is commonly used to diagnose disease and is consistently associated with increased mortality in critically ill patients.", "However, the molecular controls of elevated body temperature are poorly understood.", "We discovered that the expression of RNA-binding motif protein 3 (RBM3), known to respond to cold stress and to modulate microRNA (miRNA) expression, was reduced in 30 patients with fever, and in THP-1-derived macrophages maintained at a fever-like temperature (40 °C).", "Notably, RBM3 expression is reduced during fever whether or not infection is demonstrable.", "Reduced RBM3 expression resulted in increased expression of RBM3-targeted temperature-sensitive miRNAs, we termed thermomiRs.", "ThermomiRs such as miR-142-5p and miR-143 in turn target endogenous pyrogens including IL-6, IL6ST, TLR2, PGE2 and TNF to complete a negative feedback mechanism, which may be crucial to prevent pathological hyperthermia.", "Using normal PBMCs that were exogenously exposed to fever-like temperature (40 °C), we further demonstrate the trend by which decreased levels of RBM3 were associated with increased levels of miR-142-5p and miR-143 and vice versa over a 24 h time course.", "Collectively, our results indicate the existence of a negative feedback loop that regulates fever via reduced RBM3 levels and increased expression of miR-142-5p and miR-143." ]

[ 5 ]

[ "Fever is commonly used to diagnose disease and is consistently associated with increased mortality in critically ill patients.", "However, the molecular controls of elevated body temperature are poorly understood.", "We discovered that the expression of RNA-binding motif protein 3 (RBM3), known to respond to cold stress and to modulate microRNA (miRNA) expression, was reduced in 30 patients with fever, and in THP-1-derived macrophages maintained at a fever-like temperature (40 °C).", "Notably, RBM3 expression is reduced during fever whether or not infection is demonstrable.", "Reduced RBM3 expression resulted in increased expression of RBM3-targeted temperature-sensitive miRNAs, we termed thermomiRs.", "ThermomiRs such as miR-142-5p and miR-143 in turn target endogenous pyrogens including IL-6, IL6ST, TLR2, PGE2 and TNF to complete a negative feedback mechanism, which may be crucial to prevent pathological hyperthermia.", "Using normal PBMCs that were exogenously exposed to fever-like temperature (40 °C), we further demonstrate the trend by which decreased levels of RBM3 were associated with increased levels of miR-142-5p and miR-143 and vice versa over a 24 h time course.", "Collectively, our results indicate the existence of a negative feedback loop that regulates fever via reduced RBM3 levels and increased expression of miR-142-5p and miR-143." ]

[ 4, 5 ]

[ "MicroRNAs (miRNAs) are short, highly conserved noncoding RNA molecules that repress gene expression in a sequence-dependent manner.", "We performed single-cell measurements using quantitative fluorescence microscopy and flow cytometry to monitor a target gene's protein expression in the presence and absence of regulation by miRNA.", "We find that although the average level of repression is modest, in agreement with previous population-based measurements, the repression among individual cells varies dramatically.", "In particular, we show that regulation by miRNAs establishes a threshold level of target mRNA below which protein production is highly repressed.", "Near this threshold, protein expression responds sensitively to target mRNA input, consistent with a mathematical model of molecular titration.", "These results show that miRNAs can act both as a switch and as a fine-tuner of gene expression." ]

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[ "Biological systems use a variety of mechanisms to maintain their functions in the face of environmental and genetic perturbations.", "Increasing evidence suggests that, among their roles as posttranscriptional repressors of gene expression, microRNAs (miRNAs) help to confer robustness to biological processes by reinforcing transcriptional programs and attenuating aberrant transcripts, and they may in some network contexts help suppress random fluctuations in transcript copy number.", "These activities have important consequences for normal development and physiology, disease, and evolution.", "Here, we will discuss examples and principles of miRNAs that contribute to robustness in animal systems." ]

[ 1 ]

[ "Emerging data suggest that microRNAs (miRNAs) are instrumental in a variety of stress responses in addition to their more recognized role in development.", "Surprisingly, miRNAs, which normally suppress expression of target transcripts, may become activators of expression during stress.", "This might be partially explained by new interactions of miRNA/Argonaute complexes with RNA-binding proteins that relocate from different subcellular compartments during stress." ]

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[ "Monitoring cancer and aging in vivo remains experimentally challenging.", "Here, we describe a luciferase knockin mouse (p16(LUC)), which faithfully reports expression of p16(INK4a), a tumor suppressor and aging biomarker.", "Lifelong assessment of luminescence in p16(+/LUC) mice revealed an exponential increase with aging, which was highly variable in a cohort of contemporaneously housed, syngeneic mice.", "Expression of p16(INK4a) with aging did not predict cancer development, suggesting that the accumulation of senescent cells is not a principal determinant of cancer-related death.", "In 14 of 14 tested tumor models, expression of p16(LUC) was focally activated by early neoplastic events, enabling visualization of tumors with sensitivity exceeding other imaging modalities.", "Activation of p16(INK4a) was noted in the emerging neoplasm and surrounding stromal cells.", "This work suggests that p16(INK4a) activation is a characteristic of all emerging cancers, making the p16(LUC) allele a sensitive, unbiased reporter of neoplastic transformation." ]

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[ "Monitoring cancer and aging in vivo remains experimentally challenging.", "Here, we describe a luciferase knockin mouse (p16(LUC)), which faithfully reports expression of p16(INK4a), a tumor suppressor and aging biomarker.", "Lifelong assessment of luminescence in p16(+/LUC) mice revealed an exponential increase with aging, which was highly variable in a cohort of contemporaneously housed, syngeneic mice.", "Expression of p16(INK4a) with aging did not predict cancer development, suggesting that the accumulation of senescent cells is not a principal determinant of cancer-related death.", "In 14 of 14 tested tumor models, expression of p16(LUC) was focally activated by early neoplastic events, enabling visualization of tumors with sensitivity exceeding other imaging modalities.", "Activation of p16(INK4a) was noted in the emerging neoplasm and surrounding stromal cells.", "This work suggests that p16(INK4a) activation is a characteristic of all emerging cancers, making the p16(LUC) allele a sensitive, unbiased reporter of neoplastic transformation." ]

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[ "The multifunctional signaling protein p75 neurotrophin receptor (p75(NTR)) is a central regulator and major contributor to the highly invasive nature of malignant gliomas.", "Here, we show that neurotrophin-dependent regulated intramembrane proteolysis (RIP) of p75(NTR) is required for p75(NTR)-mediated glioma invasion, and identify a previously unnamed process for targeted glioma therapy.", "Expression of cleavage-resistant chimeras of p75(NTR) or treatment of animals bearing p75(NTR)-positive intracranial tumors with clinically applicable gamma-secretase inhibitors resulted in dramatically decreased glioma invasion and prolonged survival.", "Importantly, proteolytic processing of p75(NTR) was observed in p75(NTR)-positive patient tumor specimens and brain tumor initiating cells.", "This work highlights the importance of p75(NTR) as a therapeutic target, suggesting that gamma-secretase inhibitors may have direct clinical application for the treatment of malignant glioma." ]

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[ "Importance The Sepsis-3 Criteria emphasized the value of a change of 2 or more points in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, introduced quick SOFA (qSOFA), and removed the systemic inflammatory response syndrome (SIRS) criteria from the sepsis definition.", "Objective Externally validate and assess the discriminatory capacities of an increase in SOFA score by 2 or more points, 2 or more SIRS criteria, or a qSOFA score of 2 or more points for outcomes among patients who are critically ill with suspected infection.", "Design, Setting, and Participants Retrospective cohort analysis of 184 875 patients with an infection-related primary admission diagnosis in 182 Australian and New Zealand intensive care units (ICUs) from 2000 through 2015.", "Exposures SOFA, qSOFA, and SIRS criteria applied to data collected within 24 hours of ICU admission.", "Main Outcomes and Measures The primary outcome was in-hospital mortality.", "In-hospital mortality or ICU length of stay (LOS) of 3 days or more was a composite secondary outcome.", "Discrimination was assessed using the area under the receiver operating characteristic curve (AUROC).", "Adjusted analyses were performed using a model of baseline risk determined using variables independent of the scoring systems.", "Results Among 184 875 patients (mean age, 62.9 years [SD, 17.4]; women, 82 540 [44.6%]; most common diagnosis bacterial pneumonia, 32 634 [17.7%]), a total of 34 578 patients (18.7%) died in the hospital, and 102 976 patients (55.7%) died or experienced an ICU LOS of 3 days or more.", "SOFA score increased by 2 or more points in 90.1%; 86.7% manifested 2 or more SIRS criteria, and 54.4% had a qSOFA score of 2 or more points.", "SOFA demonstrated significantly greater discrimination for in-hospital mortality (crude AUROC, 0.753 [99% CI, 0.750-0.757]) than SIRS criteria (crude AUROC, 0.589 [99% CI, 0.585-0.593]) or qSOFA (crude AUROC, 0.607 [99% CI, 0.603-0.611]).", "Incremental improvements were 0.164 (99% CI, 0.159-0.169) for SOFA vs SIRS criteria and 0.146 (99% CI, 0.142-0.151) for SOFA vs qSOFA (P <.001).", "SOFA (AUROC, 0.736 [99% CI, 0.733-0.739]) outperformed the other scores for the secondary end point (SIRS criteria: AUROC, 0.609 [99% CI, 0.606-0.612]; qSOFA: AUROC, 0.606 [99% CI, 0.602-0.609]).", "Incremental improvements were 0.127 (99% CI, 0.123-0.131) for SOFA vs SIRS criteria and 0.131 (99% CI, 0.127-0.134) for SOFA vs qSOFA (P <.001).", "Findings were consistent for both outcomes in multiple sensitivity analyses.", "Conclusions and Relevance Among adults with suspected infection admitted to an ICU, an increase in SOFA score of 2 or more had greater prognostic accuracy for in-hospital mortality than SIRS criteria or the qSOFA score.", "These findings suggest that SIRS criteria and qSOFA may have limited utility for predicting mortality in an ICU setting." ]

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[ "Biogenesis of ribosomes is an essential cellular process conserved across all eukaryotes and is known to require >170 genes for the assembly, modification, and trafficking of ribosome components through multiple cellular compartments.", "Despite intensive study, this pathway likely involves many additional genes.", "Here, we employ network-guided genetics-an approach for associating candidate genes with biological processes that capitalizes on recent advances in functional genomic and proteomic studies-to computationally identify additional ribosomal biogenesis genes.", "We experimentally evaluated >100 candidate yeast genes in a battery of assays, confirming involvement of at least 15 new genes, including previously uncharacterized genes (YDL063C, YIL091C, YOR287C, YOR006C/TSR3, YOL022C/TSR4).", "We associate the new genes with specific aspects of ribosomal subunit maturation, ribosomal particle association, and ribosomal subunit nuclear export, and we identify genes specifically required for the processing of 5S, 7S, 20S, 27S, and 35S rRNAs.", "These results reveal new connections between ribosome biogenesis and mRNA splicing and add >10% new genes-most with human orthologs-to the biogenesis pathway, significantly extending our understanding of a universally conserved eukaryotic process." ]

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[ "Glioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioblastoma stem cells (GSCs).", "GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutic targets.", "We determined that A20 (TNFAIP3), a regulator of cell survival and the NF-kappaB pathway, is overexpressed in GSCs relative to non-stem glioblastoma cells at both the mRNA and protein levels.", "To determine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediated delivery of short hairpin RNA (shRNA).", "Inhibiting A20 expression decreased GSC growth and survival through mechanisms associated with decreased cell-cycle progression and decreased phosphorylation of p65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptible to TNFalpha-induced cell death than matched non-stem glioma cells, but A20 knockdown sensitized GSCs to TNFalpha-mediated apoptosis.", "The decreased survival of GSCs upon A20 knockdown contributed to the reduced ability of these cells to self-renew in primary and secondary neurosphere formation assays.", "The tumorigenic potential of GSCs was decreased with A20 targeting, resulting in increased survival of mice bearing human glioma xenografts.", "In silico analysis of a glioma patient genomic database indicates that A20 overexpression and amplification is inversely correlated with survival.", "Together these data indicate that A20 contributes to glioma maintenance through effects on the glioma stem cell subpopulation.", "Although inactivating mutations in A20 in lymphoma suggest A20 can act as a tumor suppressor, similar point mutations have not been identified through glioma genomic sequencing: in fact, our data suggest A20 may function as a tumor enhancer in glioma through promotion of GSC survival.", "A20 anticancer therapies should therefore be viewed with caution as effects will likely differ depending on the tumor type." ]

[ 6 ]

[ "OBJECTIVE A20 is a TNF-inducible primary response gene, which has been found to have antiapoptotic function in several cancer cells.", "This study investigates A20 expression in human glioma tissues and four glioma cell lines, and its effect on tumorigenesis of glioma cells and a mouse tumor model.", "METHODS Human glioma tissue samples and cells were subject to reverse transcription-PCR (RT-PCR), western blotting and immunohistochemistry.", "Glioma cells was tested by flow cytometry.", "A xenograft tumor model in mice was utilized to examine the knock-down effect of specific A20 siRNAs on tumorigenesis.", "RESULTS A20 was overexpressed in clinical glioma tissue samples (63.9%) and correlated with clinical staging.", "All four human glioma cell lines expressed A20, among which U87 displayed the strongest expression signals.", "Inhibiting A20 expression by siRNAs in vitro reduced the growth rates of glioma cells and resulted in G1/S arrest and increased apoptosis.", "In a mouse tumor model, local administration of siRNA significantly suppressed solid tumor growth.", "CONCLUSIONS A20 was overexpressed both in human glioma tissues and cell lines, and inhibiting A20 expression greatly slowed tumor cell growth in culture and in mice.", "These findings indicated that A20 is involved in tumorigenesis of human glioma, and may serve as a future therapeutic target." ]

[ 7, 8, 9 ]

[ "Glioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioblastoma stem cells (GSCs).", "GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutic targets.", "We determined that A20 (TNFAIP3), a regulator of cell survival and the NF-kappaB pathway, is overexpressed in GSCs relative to non-stem glioblastoma cells at both the mRNA and protein levels.", "To determine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediated delivery of short hairpin RNA (shRNA).", "Inhibiting A20 expression decreased GSC growth and survival through mechanisms associated with decreased cell-cycle progression and decreased phosphorylation of p65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptible to TNFalpha-induced cell death than matched non-stem glioma cells, but A20 knockdown sensitized GSCs to TNFalpha-mediated apoptosis.", "The decreased survival of GSCs upon A20 knockdown contributed to the reduced ability of these cells to self-renew in primary and secondary neurosphere formation assays.", "The tumorigenic potential of GSCs was decreased with A20 targeting, resulting in increased survival of mice bearing human glioma xenografts.", "In silico analysis of a glioma patient genomic database indicates that A20 overexpression and amplification is inversely correlated with survival.", "Together these data indicate that A20 contributes to glioma maintenance through effects on the glioma stem cell subpopulation.", "Although inactivating mutations in A20 in lymphoma suggest A20 can act as a tumor suppressor, similar point mutations have not been identified through glioma genomic sequencing: in fact, our data suggest A20 may function as a tumor enhancer in glioma through promotion of GSC survival.", "A20 anticancer therapies should therefore be viewed with caution as effects will likely differ depending on the tumor type." ]

[ 6 ]

[ "OBJECTIVE A20 is a TNF-inducible primary response gene, which has been found to have antiapoptotic function in several cancer cells.", "This study investigates A20 expression in human glioma tissues and four glioma cell lines, and its effect on tumorigenesis of glioma cells and a mouse tumor model.", "METHODS Human glioma tissue samples and cells were subject to reverse transcription-PCR (RT-PCR), western blotting and immunohistochemistry.", "Glioma cells was tested by flow cytometry.", "A xenograft tumor model in mice was utilized to examine the knock-down effect of specific A20 siRNAs on tumorigenesis.", "RESULTS A20 was overexpressed in clinical glioma tissue samples (63.9%) and correlated with clinical staging.", "All four human glioma cell lines expressed A20, among which U87 displayed the strongest expression signals.", "Inhibiting A20 expression by siRNAs in vitro reduced the growth rates of glioma cells and resulted in G1/S arrest and increased apoptosis.", "In a mouse tumor model, local administration of siRNA significantly suppressed solid tumor growth.", "CONCLUSIONS A20 was overexpressed both in human glioma tissues and cell lines, and inhibiting A20 expression greatly slowed tumor cell growth in culture and in mice.", "These findings indicated that A20 is involved in tumorigenesis of human glioma, and may serve as a future therapeutic target." ]

[ 7, 8, 9 ]

[ "Plants have evolved a tremendous ability to respond to environmental changes by adapting their growth and development.", "The interaction between hormonal and developmental signals is a critical mechanism in the generation of this enormous plasticity.", "A good example is the response to the hormone ethylene that depends on tissue type, developmental stage, and environmental conditions.", "By characterizing the Arabidopsis wei8 mutant, we have found that a small family of genes mediates tissue-specific responses to ethylene.", "Biochemical studies revealed that WEI8 encodes a long-anticipated tryptophan aminotransferase, TAA1, in the essential, yet genetically uncharacterized, indole-3-pyruvic acid (IPA) branch of the auxin biosynthetic pathway.", "Analysis of TAA1 and its paralogues revealed a link between local auxin production, tissue-specific ethylene effects, and organ development.", "Thus, the IPA route of auxin production is key to generating robust auxin gradients in response to environmental and developmental cues." ]

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[ "Membrane attack complex/perforin-like (MACPF) proteins comprise the largest superfamily of pore-forming proteins, playing crucial roles in immunity and pathogenesis.", "Soluble monomers assemble into large transmembrane pores via conformational transitions that remain to be structurally and mechanistically characterised.", "Here we present an 11 Å resolution cryo-electron microscopy (cryo-EM) structure of the two-part, fungal toxin Pleurotolysin (Ply), together with crystal structures of both components (the lipid binding PlyA protein and the pore-forming MACPF component PlyB).", "These data reveal a 13-fold pore 80 Å in diameter and 100 Å in height, with each subunit comprised of a PlyB molecule atop a membrane bound dimer of PlyA. The resolution of the EM map, together with biophysical and computational experiments, allowed confident assignment of subdomains in a MACPF pore assembly.", "The major conformational changes in PlyB are a ∼70° opening of the bent and distorted central β-sheet of the MACPF domain, accompanied by extrusion and refolding of two α-helical regions into transmembrane β-hairpins (TMH1 and TMH2).", "We determined the structures of three different disulphide bond-trapped prepore intermediates.", "Analysis of these data by molecular modelling and flexible fitting allows us to generate a potential trajectory of β-sheet unbending.", "The results suggest that MACPF conformational change is triggered through disruption of the interface between a conserved helix-turn-helix motif and the top of TMH2.", "Following their release we propose that the transmembrane regions assemble into β-hairpins via top down zippering of backbone hydrogen bonds to form the membrane-inserted β-barrel.", "The intermediate structures of the MACPF domain during refolding into the β-barrel pore establish a structural paradigm for the transition from soluble monomer to pore, which may be conserved across the whole superfamily.", "The TMH2 region is critical for the release of both TMH clusters, suggesting why this region is targeted by endogenous inhibitors of MACPF function." ]

[ 4 ]

[ "The microtubule (MT) cytoskeleton is required for many aspects of cell function, including the transport of intracellular materials, the maintenance of cell polarity, and the regulation of mitosis.", "These functions are coordinated by MT-associated proteins (MAPs), which work in concert with each other, binding MTs and altering their properties.", "We have used a MT cosedimentation assay, combined with 1D and 2D PAGE and mass spectrometry, to identify over 250 MAPs from early Drosophila embryos.", "We have taken two complementary approaches to analyse the cellular function of novel MAPs isolated using this approach.", "First, we have carried out an RNA interference (RNAi) screen, identifying 21 previously uncharacterised genes involved in MT organisation.", "Second, we have undertaken a bioinformatics analysis based on binary protein interaction data to produce putative interaction networks of MAPs.", "By combining both approaches, we have identified and validated MAP complexes with potentially important roles in cell cycle regulation and mitosis.", "This study therefore demonstrates that biologically relevant data can be harvested using such a multidisciplinary approach, and identifies new MAPs, many of which appear to be important in cell division." ]

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[ "The P446L mutant Drosophila importin-beta (P446L-imp-beta) has been reported to prohibit--in dominant negative fashion--nuclear envelope (NE) assembly.", "Along elucidating the mode of action of P446L-imp-beta we studied in vitro NE assembly on Sepharose beads.", "While Drosophila embryo extracts support NE assembly over Sepharose beads coated with Ran, NE assembly does not take place in extracts supplied with exogenous P446L-imp-beta.", "A NE also forms over importin-beta-coated beads.", "Surprisingly, when immobilized to Sepharose beads P446L-imp-beta as efficiently recruits NE vesicles as normal importin-beta.", "The discrepancy in behavior of cytoplasmic and bead-bound P446L-imp-beta appears to be related to icreased--as compared to normal importin-beta--microtubule (MT) binding ability of P446L-imp-beta.", "While wild-type importin-beta is able to bind MTs and the binding decreases upon RanGTP interaction, P446L-imp-beta cannot be removed from the MTs by RanGTP.", "P446L-imp-beta, like normal importin-beta, binds some types of the nucleoporins that have been known to be required for NE assembly at the end of mitosis.", "It appears that the inhibitory effect of P446L-imp-beta on NE assembly is caused by sequestering some of the nucleoporins required for NE assembly to the MTs." ]

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