Journal articles: 'Dbr1p'

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Salem, Laura A., Christopher L. Boucher, and Thomas M. Menees. "Relationship between RNA Lariat Debranching and Ty1 Element Retrotransposition." Journal of Virology 77, no. 23 (December 1, 2003): 12795–806. http://dx.doi.org/10.1128/jvi.77.23.12795-12806.2003.

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ABSTRACT The Saccharomyces cerevisiae DBR1 gene encodes a 2′-5′ phosphodiesterase that debranches intron RNA lariats following splicing. Yeast dbr1 mutants accumulate intron lariats and are also defective for mobility of the retrotransposons Ty1 and Ty3. We used a mutagenic PCR method to generate a collection of dbr1 mutant alleles to explore the relationship between the roles of DBR1 in transposition and debranching. Eight mutants defective for Ty1 transposition contained single amino acid changes in Dbr1p. Two mutations, G84A and N85D, are in a conserved phosphoesterase motif that is believed to be part of the active site of the enzyme, supporting a connection between enzymatic activity and Ty1 transposition. Two other mutations, Y68F and Y68D, occur at a potential phosphorylation site, and we have shown that Dbr1p is phosphorylated on tyrosine. We have developed an RNase protection assay to quantitate intron RNA accumulation in cells. The assay uses RNA probes that hybridize to ACT1 intron RNA. Protection patterns confirm that sequences from the 5′ end of the intron to the lariat branch point accumulate in dbr1 mutants in a branched (lariat) conformation. RNase protection assays indicate that all of the newly generated dbr1 mutant alleles are also deficient for debranching, further supporting a role for 2′-5′ phosphodiesterase activity in Ty1 transposition. A Ty1 element lacking most of its internal sequences transposes independently of DBR1. The existence of Dbr1p-dependent Ty1 sequences raises the possibility that Dbr1p acts on Ty1 RNA.

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Karst, Stephanie M., Marie-Louise Rütz, and Thomas M. Menees. "The Yeast Retrotransposons Ty1 and Ty3 Require the RNA Lariat Debranching Enzyme, Dbr1p, for Efficient Accumulation of Reverse Transcripts." Biochemical and Biophysical Research Communications 268, no. 1 (February 2000): 112–17. http://dx.doi.org/10.1006/bbrc.1999.2048.

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Menees, Thomas M. "Saccharomyces cerevisiae RNA lariat debranching enzyme, Dbr1p, is required for completion of reverse transcription by the retrovirus-like element Ty1 and cleaves branched Ty1 RNAs." Molecular Genetics and Genomics 296, no. 2 (January 19, 2021): 409–22. http://dx.doi.org/10.1007/s00438-020-01753-y.

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FABER, A. W. "The RNA catabolic enzymes Rex4p, Rnt1p, and Dbr1p show genetic interaction with trans-acting factors involved in processing of ITS1 in Saccharomyces cerevisiae pre-rRNA." RNA 10, no. 12 (December 1, 2004): 1946–56. http://dx.doi.org/10.1261/rna.7155904.

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Xu, Xiaoqin, Xin Yang, Xue Liu, Yanghui Bi, Pengzhou Kong, Yanqiang Wang, Xiaolong Cheng, and Yanfeng Xi. "The Role of DBR1 as a Candidate Prognosis Biomarker in Esophageal Squamous Cell Carcinoma." Technology in Cancer Research & Treatment 21 (January 2022): 153303382210831. http://dx.doi.org/10.1177/15330338221083105.

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Aims: Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent malignancies with unfavorable clinical outcomes and limited therapeutic methods. As a key enzyme in RNA metabolism, debranching RNA Lariats 1 (DBR1) is involved in intron turnover and biogenesis of noncoding RNA. Although cancer cells often show disorder of nucleic acid metabolism, it is unclear whether DBR1 has any effect on the carcinogenesis and progression of ESCC. Methods: Here we detected DBR1 expression in 112 ESCC samples by immunohistochemistry and analyzed its correlation with clinical parameters and survival. Results: DBR1 is mainly located in the nucleus of ESCC tissue. And DBR1 was associated with several malignant clinical features in patients, including tumor location ( χ2 = 9.687, P = .021), pathologic T stage ( χ2 = 5.771, P = .016), lymph node metastasis ( χ2 = 8.215, P = .004) and N classification ( χ2 = 10.066, P = .018). Moreover, Kaplan-Meier analysis showed that ESCC patients harboring lower DBR1 expression had a worse prognosis in comparison with those with higher DBR1 expression ( P = .005). Univariate and multivariate Cox proportional hazards regression analyses indicated that decreased DBR1 might act as an independent predictor of poor prognosis for ESCC patients. Conclusion: Abnormal RNA metabolism might play a critical role in promoting the progression of ESCC, and DBR1 may be a promising potential biomarker for predicting the prognosis of ESCC patients.

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Chen, G. C., L. Zheng, and C. S. Chan. "The LIM domain-containing Dbm1 GTPase-activating protein is required for normal cellular morphogenesis in Saccharomyces cerevisiae." Molecular and Cellular Biology 16, no. 4 (April 1996): 1376–90. http://dx.doi.org/10.1128/mcb.16.4.1376.

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Normal cell growth in the yeast Saccharomyces cerevisiae involves the selection of genetically determined bud sites where most growth is localized. Previous studies have shown that BEM2, which encodes a GTPase-activating protein (GAP) that is specific for the Rho-type GTPase Rho1p in vitro, is required for proper bud site selection and bud emergence. We show here that DBM1, which encodes another putative Rho-type GAP with two tandemly arranged cysteine-rich LIM domains, also is needed for proper bud site selection, as haploid cells lacking Dbm1p bud predominantly in a bipolar, rather than the normal axial, manner. Furthermore, yeast cells lacking both Bem2p and Dbm1p are inviable. The nonaxial budding defect of dbm1 mutants can be rescued partially by overproduction of Bem3p and is exacerbated by its absence. Since Bem3p has previously been shown to function as a GAP for Cdc42p, and also less efficiently for Rho1p, our results suggest that Dbm1p, like Bem2p and Bem3p, may function in vivo as a GAP for Cdc42p and/or Rho1p. Both LIM domains of Dbm1p are essential for its normal function. Point mutations that alter single conserved cysteine residues within either LIM domain result in mutant forms of Dbm1p that can no longer function in bud site selection but instead are capable of rescuing the inviability of bem2 mutants at 35 degrees C.

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Clark, Nathaniel E., Adam Katolik, Kenneth M. Roberts, Alexander B. Taylor, Stephen P. Holloway, Jonathan P. Schuermann, Eric J. Montemayor, et al. "Metal dependence and branched RNA cocrystal structures of the RNA lariat debranching enzyme Dbr1." Proceedings of the National Academy of Sciences 113, no. 51 (December 6, 2016): 14727–32. http://dx.doi.org/10.1073/pnas.1612729114.

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Intron lariats are circular, branched RNAs (bRNAs) produced during pre-mRNA splicing. Their unusual chemical and topological properties arise from branch-point nucleotides harboring vicinal 2′,5′- and 3′,5′-phosphodiester linkages. The 2′,5′-bonds must be hydrolyzed by the RNA debranching enzyme Dbr1 before spliced introns can be degraded or processed into small nucleolar RNA and microRNA derived from intronic RNA. Here, we measure the activity of Dbr1 fromEntamoeba histolyticaby using a synthetic, dark-quenched bRNA substrate that fluoresces upon hydrolysis. Purified enzyme contains nearly stoichiometric equivalents of Fe and Zn per polypeptide and demonstrates turnover rates of ∼3 s−1. Similar rates are observed when apo-Dbr1 is reconstituted with Fe(II)+Zn(II) under aerobic conditions. Under anaerobic conditions, a rate of ∼4.0 s−1is observed when apoenzyme is reconstituted with Fe(II). In contrast, apo-Dbr1 reconstituted with Mn(II) or Fe(II) under aerobic conditions is inactive. Diffraction data from crystals of purified enzyme using X-rays tuned to the Fe absorption edge show Fe partitions primarily to the β-pocket and Zn to the α-pocket. Structures of the catalytic mutant H91A in complex with 7-mer and 16-mer synthetic bRNAs reveal bona fide RNA branchpoints in the Dbr1 active site. A bridging hydroxide is in optimal position for nucleophilic attack of the scissile phosphate. The results clarify uncertainties regarding structure/function relationships in Dbr1 enzymes, and the fluorogenic probe permits high-throughput screening for inhibitors that may hold promise as treatments for retroviral infections and neurodegenerative disease.

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Nam, K., G. Lee, J. Trambley, S. E. Devine, and J. D. Boeke. "Severe growth defect in a Schizosaccharomyces pombe mutant defective in intron lariat degradation." Molecular and Cellular Biology 17, no. 2 (February 1997): 809–18. http://dx.doi.org/10.1128/mcb.17.2.809.

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The cDNAs and genes encoding the intron lariat-debranching enzyme were isolated from the nematode Caenorhabditis elegans and the fission yeast Schizosaccharomyces pombe based on their homology with the Saccharomyces cerevisiae gene. The cDNAs were shown to be functional in an interspecific complementation experiment; they can complement an S. cerevisiae dbr1 null mutant. About 2.5% of budding yeast S. cerevisiae genes have introns, and the accumulation of excised introns in a dbr1 null mutant has little effect on cell growth. In contrast, many S. pombe genes contain introns, and often multiple introns per gene, so that S. pombe is estimated to contain approximately 40 times as many introns as S. cerevisiae. The S. pombe dbr1 gene was disrupted and shown to be nonessential. Like the S. cerevisiae mutant, the S. pombe null mutant accumulated introns to high levels, indicating that intron lariat debranching represents a rate-limiting step in intron degradation in both species. Unlike the S. cerevisiae mutant, the S. pombe dbr1::leu1+ mutant had a severe growth defect and exhibited an aberrant elongated cell shape in addition to an intron accumulation phenotype. The growth defect of the S. pombe dbr1::leu1+ strain suggests that debranching activity is critical for efficient intron RNA degradation and that blocking this pathway interferes with cell growth.

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Utkin, I., D. D. Dalton, and J. Wiegel. "Specificity of Reductive Dehalogenation of Substituted ortho-Chlorophenols by Desulfitobacterium dehalogenans JW/IU-DC1." Applied and Environmental Microbiology 61, no. 4 (April 1995): 1677. http://dx.doi.org/10.1128/aem.61.4.1677-1677c.1995.

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Volume 61, no. 1, abstract, lines 4 and 5: "2,6-dichloro-4-R-phenols, where . . ." should read "2,6-dichloro-4-R-phenols (2,6-DCl-4-RPs, where R is -H, -F, -Cl, -NO(inf2), -CO(inf2)(sup-), or -COOCH(inf3)) . . ." Line 6: ". . . bromophenols (2-BrP, 2,6-DBrP, and 2-Br-4ClP)" should read ". . . the bromophenols 2-BrP, 2,6-DBrP, and 2-Br-4-ClP." [This corrects the article on p. 346 in vol. 61.].

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Zhang, Yansheng, Keat H. Teoh, Darwin W. Reed, and Patrick S. Covello. "Molecular cloning and characterization of Dbr1, a 2-alkenal reductase from Artemisia annuaThe nucleotide sequence reported in this article has been deposited in the GenBank database under accession No. FJ750460.This paper is one of a selection of papers published in a Special Issue from the National Research Council of Canada – Plant Biotechnology Institute." Botany 87, no. 6 (June 2009): 643–49. http://dx.doi.org/10.1139/b09-033.

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The molecular genetics of carbon–carbon double bond reduction in the plant Artemisia annua L. was studied. Expressed sequence tags from this plant were investigated for sequences with similarity to known double-bond reductases. This resulted in the isolation of a cDNA, corresponding to the gene A. annua Dbr1 (Double bond reductase1), encoding a member of the medium chain dehydrogenase/reductase protein superfamily with sequence similarity to tobacco allyl alcohol dehydrogenase. Recombinant A. annua Dbr1 protein was purified from Escherischia coli and shown to catalyze the reduction of the carbon–carbon double bond of 2-alkenals. This activity included the reduction of the double bond at C11–C13 in the artemisinin precursor artemisinic aldehyde, albeit with unnatural stereochemistry. The substrate specificity, product stereochemistry, and expression pattern of A. annua Dbr1 point to its involvement in planta in the detoxification of 2-alkenals, which may be generated under oxidative stress conditions.

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Menees, Thomas M. "RNA Lariat Debranching Enzyme as a Retroviral and Long-Terminal-Repeat Retrotransposon Host Factor." Annual Review of Virology 7, no. 1 (September 29, 2020): 189–202. http://dx.doi.org/10.1146/annurev-virology-012720-094902.

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Host cell factors are integral to viral replication. Human immunodeficiency virus 1 (HIV-1), the retroviral agent of acquired immune deficiency syndrome, requires several host factors for reverse transcription of the viral genomic RNA (gRNA) into DNA shortly after viral entry. One of these host factors is the RNA lariat debranching enzyme (Dbr1), which cleaves the 2′–5′ bond of branched and lariat RNAs. A recent study has revealed that Dbr1 cleaves HIV-1 gRNA lariats that form early after viral entry. Without Dbr1 activity, HIV-1 reverse transcription stalls, consistent with blockage of viral reverse transcriptase at gRNA branch points. These findings echo an earlier study with the long-terminal-repeat retrotransposon of Saccharomyces cerevisiae, Ty1, which is a retrovirus model. Currently, branching and debranching of viral gRNA are not widely recognized as features of HIV-1 replication, and the role of a gRNA lariat is not known. Future studies will determine whether these gRNA dynamics represent fundamental features of retroviral biology and whether they occur for other positive-sense RNA viruses.

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Bogan, Richard, Yves Dauvilliers, Michael Thorpy, Patricia Chandler, Abby Chen, Dan Chen, and Isabelle Arnulf. "487 Effect of Lower-Sodium Oxybate on Sleep Inertia in Idiopathic Hypersomnia in a Double-Blind, Randomized Withdrawal Study." Sleep 44, Supplement_2 (May 1, 2021): A192. http://dx.doi.org/10.1093/sleep/zsab072.486.

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Abstract Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder characterized by excessive daytime sleepiness. A common feature is sleep inertia, which is prolonged difficulty waking up accompanied by confusion, disorientation, poor motor coordination, and repeated returns to sleep. Sleep inertia is burdensome to patients, resulting in missed work or school, and patients may be dependent on others to wake them. No treatment is currently approved for IH. The efficacy and safety of lower-sodium oxybate (LXB; Xywav™), a novel oxybate treatment with 92% less sodium than sodium oxybate (Xyrem®), was evaluated in a phase 3 study (NCT03533114) in adults with IH. We focus here on the drug effect on sleep inertia. Methods Eligible participants aged 18–75 years with IH began LXB treatment with an open-label treatment titration and optimization period (OLTTOP; 10–14 weeks), followed by a 2-week, open-label, stable-dose period (SDP). Participants were randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The primary efficacy endpoint was change in Epworth Sleepiness Scale score. The visual analog scale for sleep inertia (VAS-SI) was included as an exploratory endpoint. The VAS-SI, administered daily during the last 2 weeks of screening before baseline, SDP, and DBRWP, is a self-reported retrospective measure of difficulty awakening each morning using a 100-mm line with anchors 0 (very easy) and 100 (very difficult). Results The safety population included 154 participants (mean±SD age, 40±14 years; 68% female); modified intent-to-treat population, n=115. VAS-SI scores gradually decreased from week 2 of screening (mean±SD, 56.6±25.1) to week 2 of SDP (29.0±20.8). During week 2 of DBRWP, VAS-SI scores worsened in participants randomized to placebo (n=59) compared with maintenance of improvement in participants continuing LXB treatment (n=56); LS mean difference (95% CI) in change from SDP, −22.2 (−29.7, −14.8); P<0.0001 (nominal). Common adverse events included nausea (21.4%), headache (16.2%), anxiety (14.9%), dizziness (11.7%), insomnia (11.7%), and vomiting (10.4%). Conclusion Sleep inertia improved with LXB treatment and significant differences were seen between placebo and LXB after DBRWP. The overall safety profile in participants with IH is consistent with that of LXB in narcolepsy. Support (if any) Jazz Pharmaceuticals, Inc

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Foldvary-Schaefer, Nancy, Isabelle Arnulf, Karel Šonka, Patricia Chandler, Abby Chen, Dan Chen, and Yves Dauvilliers. "495 Efficacy of Lower-Sodium Oxybate on Idiopathic Hypersomnia, Measured by the Idiopathic Hypersomnia Severity Scale." Sleep 44, Supplement_2 (May 1, 2021): A195. http://dx.doi.org/10.1093/sleep/zsab072.494.

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Abstract Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder with no approved treatment, characterized by excessive daytime sleepiness, prolonged sleep time, and sleep inertia. The Idiopathic Hypersomnia Severity Scale (IHSS) is a 14-item, self-reported questionnaire that assesses severity of IH symptoms, including symptoms related to night/inertia (component I) and day/performance (component II). Individual IHSS items measure symptom frequency, intensity, and consequences using 3- or 4-point Likert scales, yielding a total score (range, 0–50), comprising component I (range, 0–16) and component II (range, 0–34). Higher scores indicate worse symptoms. In a recent clinical trial of the efficacy and safety of lower-sodium oxybate (LXB; Xywav™) for the treatment of IH, the IHSS was a key efficacy measure. Methods Eligible participants 18–75 years of age with IH began LXB treatment with an open-label treatment titration and optimization period (OLTTOP; 10–14 weeks), followed by a 2-week stable-dose period (SDP). Participants were randomized to placebo or continued LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The IHSS was completed at baseline, during OLTTOP (weeks 1, 4, and 8), and at the end of OLTTOP, SDP, and DBRWP. Change in IHSS total score from SDP to DBRWP was a key secondary endpoint. Results The efficacy population included 115 participants (mean±SD age, 41±14 years; 71% female). At baseline and the end of SDP, respectively, mean±SD IHSS scores were 31.6±8.3 and 15.3±8.5 for total score, 10.3±3.6 and 5.4±2.8 for component I (night/inertia), and 21.2±5.8 and 9.9±6.5 for component II (day/performance). Worsening from SDP to DBRWP was observed in patients randomized to placebo compared with LXB in IHSS total scores (estimated median difference [95% CI], −12.0 [−15.0, −8.0]; significant P<0.0001), component I scores (LS mean difference [95% CI], −3.9 [−4.9, −2.9]; nominal P<0.0001), and component II scores (LS mean difference [95% CI], −7.8 [−9.6, −5.9]; nominal P<0.0001). Results on all individual IHSS items reflected an improvement with LXB treatment over time during OLTTOP, which remained consistent during SDP. Conclusion These results support the efficacy of LXB for the treatment of IH symptoms, as assessed with the IHSS. Support (if any) Jazz Pharmaceuticals

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Kim, J. W. "Human RNA lariat debranching enzyme cDNA complements the phenotypes of Saccharomyces cerevisiae dbr1 and Schizosaccharomyces pombe dbr1 mutants." Nucleic Acids Research 28, no. 18 (September 15, 2000): 3666–73. http://dx.doi.org/10.1093/nar/28.18.3666.

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Galvis, A. E., H. E. Fisher, T. Nitta, H. Fan, and D. Camerini. "Impairment of HIV-1 cDNA Synthesis by DBR1 Knockdown." Journal of Virology 88, no. 12 (March 26, 2014): 7054–69. http://dx.doi.org/10.1128/jvi.00704-14.

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Wang, Jianxin, Lei Song, Deepak Grover, Sami Azrak, Mark A. Batzer, and Ping Liang. "dbRIP: A highly integrated database of retrotransposon insertion polymorphisms in humans." Human Mutation 27, no. 4 (2006): 323–29. http://dx.doi.org/10.1002/humu.20307.

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Dauvilliers, Yves, Isabelle Arnulf, Nancy Foldvary-Schaefer, Patricia Chandler, Rupa Parvataneni, Dan Chen, Franck Skobieranda, and Richard Bogan. "494 Placebo-Controlled, Double-Blind, Randomized Withdrawal Study of Lower-Sodium Oxybate in Adults With Idiopathic Hypersomnia." Sleep 44, Supplement_2 (May 1, 2021): A195. http://dx.doi.org/10.1093/sleep/zsab072.493.

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Abstract Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder characterized by excessive daytime sleepiness, prolonged nighttime sleep, and sleep inertia. No US/EU medication is approved for treatment of IH. Lower-sodium oxybate (LXB; Xywav™; previously designated JZP-258) is a novel oxybate treatment with 92% less sodium than sodium oxybate (Xyrem®). The efficacy and safety of LXB was evaluated in adults with IH. Methods Eligible participants aged 18–75 years with IH began once- or twice-nightly LXB treatment entering an open-label titration and optimization period (10–14 weeks), followed by a 2-week, open-label, stable-dose period (SDP); they were then randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The primary efficacy endpoint was change in Epworth Sleepiness Scale (ESS) score; key secondary endpoints were proportion of participants who reported worsening (minimally/much/very much worse) on Patient Global Impression of Change (PGIc) and change in Idiopathic Hypersomnia Severity Scale (IHSS) score, all from end of SDP to end of DBRWP. Results The study enrolled 154 participants (mean±SD age, 40±14 years; 68% female; mean±SD ESS, 16±3.6); mean±SD dose was 6.0±1.6 g/night. Mean±SD ESS score (n=115) decreased over open-label titration/optimization (15.7±3.8 at baseline, 9.8±4.5 at week 4, and 6.1±4.0 at the end of the SDP). At the end of the DBRWP, significant worsening was observed in participants randomized to placebo, compared with maintenance of improvement in participants randomized to continue LXB, in ESS scores (n=115; LS mean difference [95% CI] in change from SDP, −6.51 [−7.99, −5.03]; P<0.0001), in the PGIc (88.1% for placebo vs 21.4% for LXB; P<0.0001), and in IHSS scores (estimated median difference [95% CI], −12.00 [−15.0, −8.0]; P<0.0001). Common adverse events (AEs) included nausea (21.4%), headache (16.2%), anxiety (14.9%), dizziness (11.7%), insomnia (11.7%), and vomiting (10.4%). Serious AEs occurred in 4 participants (non-cardiac chest pain, rhabdomyolysis, syncope, and nephrolithiasis/pyelonephritis); none were reported related to study drug. Conclusion In participants with IH, LXB demonstrated a clinically meaningful effect on excessive daytime sleepiness, self-reported global change, and overall IH symptom severity. The overall safety profile was consistent with that of LXB in narcolepsy. Support (if any) Jazz Pharmaceuticals

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Hasan, Siham, Meisam Sharifi Sani, Saeid Iranmanesh, Ali H. Al-Bayatti, Sarmadullah Khan, and Raad Raad. "Enhanced Message Replication Technique for DTN Routing Protocols." Sensors 23, no. 2 (January 13, 2023): 922. http://dx.doi.org/10.3390/s23020922.

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Delay-tolerant networks (DTNs) are networks where there is no immediate connection between the source and the destination. Instead, nodes in these networks use a store–carry–forward method to route traffic. However, approaches that rely on flooding the network with unlimited copies of messages may not be effective if network resources are limited. On the other hand, quota-based approaches are more resource-efficient but can have low delivery rates and high delivery delays. This paper introduces the Enhanced Message Replication Technique (EMRT), which dynamically adjusts the number of message replicas based on a node’s ability to quickly disseminate the message. This decision is based on factors such as current connections, encounter history, buffer size history, time-to-live values, and energy. The EMRT is applied to three different quota-based protocols: Spray and Wait, Encounter-Based Routing (EBR), and the Destination-Based Routing Protocol (DBRP). The simulation results show that applying the EMRT to these protocols improves the delivery ratio, overhead ratio, and latency average. For example, when combined with Spray and Wait, EBR, and DBRP, the delivery probability is improved by 13%, 8%, and 10%, respectively, while the latency average is reduced by 51%, 14%, and 13%, respectively.

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Mohanta, Arundhati, and Kausik Chakrabarti. "Dbr1 functions in mRNA processing, intron turnover and human diseases." Biochimie 180 (January 2021): 134–42. http://dx.doi.org/10.1016/j.biochi.2020.10.003.

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Simchen, G., K. B. Chapman, E. Caputo, K. Nam, L. Riles, D. E. Levin, and J. D. Boeke. "Mapping of DBR1 and YPK1 suggests a major revision of the genetic map of the left arm of Saccharomyces cerevisiae Chromosome XI." Genetics 138, no. 2 (October 1, 1994): 283–87. http://dx.doi.org/10.1093/genetics/138.2.283.

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Abstract The Saccharomyces cerevisiae dbr1 mutation has been mapped on the left arm of chromosome XI. XIL is a chromosome arm that was until now rather sparsely populated with accurately mapped markers. On the basis of physical data, the overall order of markers is inverted relative to the existing genetic map of XI. We present tetrad analyses using a variety of markers on XI that indicate that the existing genetic map of XIL should be inverted, at least for the strains in which our mapping was carried out, and probably for other S. cerevisiae strains.

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Montemayor, Eric J., Adam Katolik, Nathaniel E. Clark, Alexander B. Taylor, Jonathan P. Schuermann, D. Joshua Combs, Richard Johnsson, et al. "Structural basis of lariat RNA recognition by the intron debranching enzyme Dbr1." Nucleic Acids Research 42, no. 16 (August 14, 2014): 10845–55. http://dx.doi.org/10.1093/nar/gku725.

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Foldvary-Schaefer, N., M. J. Thorpy, Y. Dauvilliers, A. Roy, L. Tang, R. Skowronski, K. Šonka, and R. K. Bogan. "0740 Quality of Life in Phase 3, Placebo-Controlled, Double-Blind, Randomized Withdrawal Study of JZP-258 in Adults with Narcolepsy with Cataplexy." Sleep 43, Supplement_1 (April 2020): A281—A282. http://dx.doi.org/10.1093/sleep/zsaa056.736.

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Abstract Introduction Narcolepsy negatively impacts health-related quality of life (HRQoL). Sodium oxybate is a standard of care for the treatment of cataplexy and excessive daytime sleepiness in narcolepsy. JZP-258 is an oxybate product candidate with 92% less sodium. Efficacy and safety of JZP-258 were established in a double-blind randomized withdrawal study in adults with narcolepsy with cataplexy. Methods Participants 18-70 years of age began JZP-258 treatment during a 12-week, open-label, optimized treatment and titration period, followed by a 2-week stable-dose period (SDP). Participants were then randomized to receive placebo or continue JZP-258 treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). HRQoL assessments included the 36-Item Short Form Health Survey Version 2 (SF-36) and 5-level EuroQoL 5-Dimensions Self-Report Questionnaire (EQ-5D-5L). Results 201 participants enrolled; 134 were randomized and received at least 1 dose of double-blind study medication (efficacy population; placebo, n=65; JZP-258, n=69). Decreased scores (worsening) were observed in participants randomized to placebo compared with participants randomized to continue JZP-258 treatment for the SF-36 physical component summary (median [Q1, Q3], −1.92 [−3.46, 1.73] for placebo and −0.03 [−2.07, 2.41] for JZP-258; nominal P=0.02), SF-36 mental component summary (−1.92 [−6.28, 1.34] for placebo and 1.55 [−1.88, 3.78] for JZP-258; nominal P=0.03), and EQ-5D-5L visual analog scale (−5.00 [−10.0, 5.00] for placebo and 0 [0, 5.00] for JZP-258; nominal P=0.01). No change was observed in the EQ-5D-5L crosswalk index (0 [−0.05, 0.03] for placebo and 0 [−0.01, 0.03] for JZP-258; nominal P=0.39). The overall safety profile of JZP-258 was similar to sodium oxybate. Conclusion HRQoL worsened in those randomized to placebo during DBRWP but remained stable in participants who continued JZP-258 treatment. Support Jazz Pharmaceuticals

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Katolik, Adam, Nathaniel E. Clark, Nobuhiro Tago, Eric J. Montemayor, P. John Hart, and Masad J. Damha. "Fluorescent Branched RNAs for High-Throughput Analysis of Dbr1 Enzyme Kinetics and Inhibition." ACS Chemical Biology 12, no. 3 (January 18, 2017): 622–27. http://dx.doi.org/10.1021/acschembio.6b00971.

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Khalid, M. F. "Structure-function analysis of yeast RNA debranching enzyme (Dbr1), a manganese-dependent phosphodiesterase." Nucleic Acids Research 33, no. 19 (October 24, 2005): 6349–60. http://dx.doi.org/10.1093/nar/gki934.

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Dauvilliers, Y., N. Foldvary-Schaefer, R. K. Bogan, K. Šonka, J. Profant, L. Huang, and M. J. Thorpy. "0753 Cataplexy-Free Days in a Phase 3, Placebo-Controlled, Double-Blind, Randomized Withdrawal Study of JZP-258 in Adults With Narcolepsy With Cataplexy." Sleep 43, Supplement_1 (April 2020): A286. http://dx.doi.org/10.1093/sleep/zsaa056.749.

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Abstract Introduction Sodium oxybate (SXB) is a standard of care for the treatment of cataplexy and excessive daytime sleepiness in narcolepsy. JZP-258 is an oxybate product candidate with 92% less sodium. This analysis evaluated cataplexy-free days/week, as a measure of treatment impact, in a placebo-controlled randomized withdrawal study of JZP-258 treatment in patients with narcolepsy. Methods Treatment for cataplexy at study entry included 1) SXB (SXB-only); 2) SXB plus other anticataplectics (SXB+other); 3) anticataplectics other than SXB (other anticataplectics); or 4) cataplexy treatment-naive (anticataplectic-naive). Participants (aged 18-70 years with narcolepsy with cataplexy) began JZP-258 treatment during a 12-week, open-label, optimized treatment and titration period (OLOTTP), followed by a 2-week stable-dose period (SDP). Participants were randomized to receive placebo or continue JZP-258 treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). Results Of 201 enrolled participants, 134 comprised the efficacy population (placebo, n=65; JZP-258, n=69). Median (Q1, Q3) cataplexy-free days/week at first week of OLOTTP (while initiating JZP-258) by prior treatment were SXB-only, 5.8 (2.0, 7.0); SXB+other, 6.4 (5.0, 7.0); other anticataplectics, 4.0 (1.8, 6.0); anticataplectic-naive, 3.5 (0, 5.8). At end of SDP (on stable dose of JZP-258), median (Q1, Q3) cataplexy-free days/week were 6.0 (3.5, 7.0), 6.1 (1.4, 7.0), 6.0 (2.6, 7.0), and 6.2 (4.0, 7.0), respectively. Prior to randomization, there was no difference in median cataplexy-free days/week between participants to be randomized to placebo (6.0 [3.5, 7.0]) or JZP-258 treatment (6.0 [3.0, 7.0]); during DBRWP, median cataplexy-free days/week decreased in participants randomized to placebo (3.5 [0, 5.83]) but remained similar in participants randomized to continue JZP-258 treatment (5.6 [2.8, 7.0]). The overall safety profile of JZP-258 was similar to SXB. Conclusion Number of cataplexy-free days/week increased with JZP-258 treatment in participants previously naive to oxybate. Number of cataplexy-free days/week decreased during placebo exposure in participants randomized to placebo. Support Jazz Pharmaceuticals

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Stoll, Peter, Rüdiger Wächter, and Wolfgang Bähr. "Bridging lower jaw defects with AO plates: comparison of THORP and 3-DBRP systems." Journal of Cranio-Maxillofacial Surgery 20, no. 2 (February 1992): 87–90. http://dx.doi.org/10.1016/s1010-5182(05)80473-1.

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Dauvilliers, Yves, Isabelle Arnulf, Nancy Foldvary-Schaefer, Abby Chen, Patricia Chandler, Dan Chen, and Michael Thorpy. "500 Correlation of the Idiopathic Hypersomnia Severity Scale With Other Measures of Sleep Parameters in a Phase 3 Trial." Sleep 44, Supplement_2 (May 1, 2021): A197. http://dx.doi.org/10.1093/sleep/zsab072.499.

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Abstract Introduction The Idiopathic Hypersomnia Severity Scale (IHSS) is a 14-item, self-reported questionnaire that assesses core Idiopathic Hypersomnia (IH) symptom severity. The relationship between IHSS scores and other IH symptom measures, such as the Epworth Sleepiness Scale (ESS; measures daytime sleepiness), sleep inertia visual analog scale (VAS-SI; measures sleep inertia), and Patient Global Impression of Change (PGIc; measures patients’ self-assessed change in symptoms), has not been established. This post hoc analysis analyzed correlations between the IHSS and ESS, VAS-SI, and PGIc using data from a clinical trial (NCT03533114) evaluating lower-sodium oxybate (LXB; Xywav™) for the treatment of IH. Methods During a clinical trial, the IHSS (0–50 score range) and ESS (0–24 score range) were completed at baseline; the IHSS, ESS, and PGIc (ordinal, 7 categories) were completed during an open-label treatment titration and optimization period (OLTTOP), after the OLTTOP, after a stable-dose period (SDP), and after a double-blind, randomized withdrawal period (DBRWP). The VAS-SI (0–100 score range) was completed during screening, SDP, and DBRWP. Correlation coefficients (rs) for IHSS vs ESS and VAS-SI were estimated from the within-subject variance matrix using a repeated-measures linear mixed model (LMM). The correlation between changes in IHSS score and PGIc was assessed using a Kruskal-Wallis test. Results IHSS scores correlated positively with ESS scores (rs [95% CI], 0.77 [0.73, 0.81]) and VAS-SI scores (0.69 [0.63, 0.75]). IHSS total score change was correlated with PGIc rank (chi-square with 6 degrees of freedom = 595.8, nominal P<0.001). The LMM showed that a 3-point change in ESS score corresponded to an average 3.99-point change in IHSS score; a 10-point change in VAS-SI score corresponded to an average 3-point change in IHSS score. Participants very much improved in the PGIc had a −12.13 (95% CI: −13.23, −11.04) expected change in IHSS score. Participants much improved in the PGIc had a −8.39 (95% CI: −9.30, −7.48) expected change in IHSS score. Conclusion IHSS scores or score changes strongly correlated with individual instruments assessing excessive daytime sleepiness, sleep inertia, and self-reported global symptoms, suggesting that the IHSS is a reliable, comprehensive measure of these symptoms of IH. Support (if any) Jazz Pharmaceuticals

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Stoll, Peter, and Rüdiger Wächter. "AO reconstruction plate systems for the repair of mandibular defects 3-DBRP versus Thorp-system." Journal of Cranio-Maxillofacial Surgery 20, no. 1 (January 1992): 40–45. http://dx.doi.org/10.1016/s1010-5182(05)80195-7.

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Iranmanesh, Saeid, and Maryam Saadati. "A Novel Congestion Control Technique in Delay Tolerant Networks." International Journal of Interdisciplinary Telecommunications and Networking 10, no. 1 (January 2018): 20–35. http://dx.doi.org/10.4018/ijitn.2018010102.

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Delay Tolerant Networks (DTNs) are characterized by the lack of contemporaneous paths between any source and destination node. As a basic forwarding strategy, nodes may flood their bundles to every encountered node. This results in congestion and unnecessarily consumes precious network resources. Another strategy is to take advantage of quota based protocols in which only a limited number of copies or replicas are disseminated throughout the network in order to reduce resource usage. However, they suffer from low delivery ratios as their dissemination rate is low. In this paper, the authors propose an Adaptive Message Replication Technique (AMRT) that is fit onto quota protocols to intelligently limit the number of replicas for each generated message. In other words, a source node under AMRT considers the congestion exist amongst the neighbours in order to generate a proper number of replicas for the generated messages. The simulation studies show that when AMRT is applied onto the quota protocols namely, SprayAndWait, EBR, and DBRP, the network performance such as delivery ratio and delay is improved.

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Mösch, Hans-Ulrich, and Gerald R. Fink. "Dissection of Filamentous Growth by Transposon Mutagenesis in Saccharomyces cerevisiae." Genetics 145, no. 3 (March 1, 1997): 671–84. http://dx.doi.org/10.1093/genetics/145.3.671.

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Diploid Saccharomyces cerevisiae strains starved for nitrogen undergo a developmental transition from growth as single yeast form (YF) cells to a multicellular form consisting of filaments of pseudohyphal (PH) cells. Filamentous growth is regulated by an evolutionarily conserved signaling pathway that includes the small GTP-binding proteins Ras2p and Cdc42p, the protein kinases Ste20p, Ste11p and Ste7p, and the transcription factor Ste12p. Here, we designed a genetic screen for mutant strains defective for filamentous growth (dfg) to identify novel targets of the filamentation signaling pathway, and we thereby identified 16 different genes, CDC39, STE12, TEC1, WH13, NAB1, DBR1, CDC55, SRV2, TPM1, SPA2, BNI1, DFG5, DFG9, DFG10, BUD8 and DFG16, mutations that block filamentous growth. Phenotypic analysis of dfg mutant strains genetically dissects filamentous growth into the cellular processes of signal transduction, bud site selection, cell morphogenesis and invasive growth. Epistasis tests between dfg mutant alleles and dominant activated alleles of the RAS2 and STE11 genes, RAS2Val19 and STE11-4, respectively, identify putative targets for the filamentation signaling pathway. Several of the genes described here have homologues in filamentous fungi, where they also regulate fungal development.

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Schwer, Beate, Fahad Khalid, and Stewart Shuman. "Mechanistic insights into the manganese-dependent phosphodiesterase activity of yeast Dbr1 with bis-p-nitrophenylphosphate and branched RNA substrates." RNA 22, no. 12 (October 7, 2016): 1819–27. http://dx.doi.org/10.1261/rna.058552.116.

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Han, B., H. K. Park, T. Ching, J. Panneerselvam, H. Wang, Y. Shen, J. Zhang, et al. "Human DBR1 modulates the recycling of snRNPs to affect alternative RNA splicing and contributes to the suppression of cancer development." Oncogene 36, no. 38 (May 15, 2017): 5382–91. http://dx.doi.org/10.1038/onc.2017.150.

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Petfalski, Elisabeth, Thomas Dandekar, Yves Henry, and David Tollervey. "Processing of the Precursors to Small Nucleolar RNAs and rRNAs Requires Common Components." Molecular and Cellular Biology 18, no. 3 (March 1, 1998): 1181–89. http://dx.doi.org/10.1128/mcb.18.3.1181.

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ABSTRACT The genes encoding the small nucleolar RNA (snoRNA) species snR190 and U14 are located close together in the genome of Saccharomyces cerevisiae. Here we report that these two snoRNAs are synthesized by processing of a larger common transcript. In strains mutant for two 5′→3′ exonucleases, Xrn1p and Rat1p, families of 5′-extended forms of snR190 and U14 accumulate; these have 5′ extensions of up to 42 and 55 nucleotides, respectively. We conclude that the 5′ ends of both snR190 and U14 are generated by exonuclease digestion from upstream processing sites. In contrast to snR190 and U14, the snoRNAs U18 and U24 are excised from the introns of pre-mRNAs which encode proteins in their exonic sequences. Analysis of RNA extracted from a dbr1-Δ strain, which lacks intron lariat-debranching activity, shows that U24 can be synthesized only from the debranched lariat. In contrast, a substantial level of U18 can be synthesized in the absence of debranching activity. The 5′ ends of these snoRNAs are also generated by Xrn1p and Rat1p. The same exonucleases are responsible for the degradation of several excised fragments of the pre-rRNA spacer regions, in addition to generating the 5′ end of the 5.8S rRNA. Processing of the pre-rRNA and both intronic and polycistronic snoRNAs therefore involves common components.

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Arnulf, Isabelle, Anne Marie Morse, Patricia Chandler, Rupa Parvataneni, Dan Chen, and Yves Dauvilliers. "485 Efficacy and Safety of Once- and Twice-Nightly Dosing of Lower-Sodium Oxybate in Adults With Idiopathic Hypersomnia." Sleep 44, Supplement_2 (May 1, 2021): A191—A192. http://dx.doi.org/10.1093/sleep/zsab072.484.

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Abstract Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder. In a randomized, controlled study of lower-sodium oxybate (LXB; Xywav™) in adults with IH (NCT03533114), significant differences for LXB compared with placebo were observed in Epworth Sleepiness Scale (ESS; primary efficacy endpoint), self-reported Patient Global Impression of Change (PGIc), and IH Severity Scale (IHSS; key secondary endpoints). In this clinical study, investigators were permitted to initiate LXB dosing on a once-nightly or twice-nightly regimen. Methods Eligible participants aged 18–75 years began LXB treatment, administered once or twice nightly during an open-label treatment/titration and optimization period (OLTTOP; 10–14 weeks); dose amount/regimen could be adjusted during this period. Participants next entered a 2-week, open-label, stable-dose period (SDP), then were randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). P values are nominal for this exploratory analysis. Results Of 154 enrolled participants, 40 (26%) initiated LXB treatment on a once-nightly regimen. In the efficacy population (n=115), 27 participants were on a once-nightly regimen during SDP (48.1% of whom initiated treatment once nightly during OLTTOP) and 88 participants were on a twice-nightly regimen during SDP (86.4% of whom initiated treatment twice nightly during OLTTOP). During SDP, median (min, max) LXB total dose was 4.5 (2.5, 6) g/night (once-nightly group) and 7.5 (4.5, 9) g/night (twice-nightly group). ESS scores worsened in participants randomized to placebo vs those continuing LXB in the once-nightly group (n=11 and n=15, respectively; LS mean difference [95% CI]: −4.93 [−7.41, −2.46]; P=0.0004) and twice-nightly group (n=47 and n=41, respectively; LS mean difference [95% CI]: −7.44 [−9.15, −5.72]; P<0.0001). Worsening was also observed in PGIc (once-nightly: 81.8% [placebo] vs 26.7% [LXB]; P=0.0077; twice-nightly: 89.4% [placebo] vs 19.5% [LXB]; P<0.0001) and IHSS score (estimated median difference [95% CI], once-nightly: −9.00 [−16.0, −3.0]; P=0.0028; twice-nightly: −12.00 [−15.0, −8.0]; P<0.0001). Common adverse events included nausea (21.4%), headache (16.2%), anxiety (14.9%), dizziness (11.7%), insomnia (11.7%), and vomiting (10.4%). Conclusion The efficacy and safety of LXB in IH were demonstrated for both once-nightly and twice-nightly regimens. The majority of participants initiated and remained on a twice-nightly regimen. Support (if any) Jazz Pharmaceuticals

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Galvis, Alvaro E., Hugh E. Fisher, Hung Fan, and David Camerini. "Conformational Changes in the 5′ End of the HIV-1 Genome Dependent on the Debranching Enzyme DBR1 during Early Stages of Infection." Journal of Virology 91, no. 23 (September 20, 2017). http://dx.doi.org/10.1128/jvi.01377-17.

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ABSTRACT Previous studies in our laboratory showed that the RNA debranching enzyme (DBR1) is not required for early steps in HIV cDNA formation but is necessary for synthesis of intermediate and late cDNA products. To further characterize this effect, we evaluated the topology of the 5′ end of the HIV-1 RNA genome during early infection with and without inhibition of DBR1 synthesis. Cells were transfected with DBR1 short hairpin RNA (shRNA) followed 48 h later by infection with an HIV-1-derived vector containing an RNase H-deficient reverse transcriptase (RT). RNA was isolated at several times postinfection and treated with various RNA-modifying enzymes prior to rapid amplification of 5′ cDNA ends (5′ RACE) for HIV-1 RNA and quantitative reverse transcriptase PCR (qRT-PCR). In infected cells, DBR1 knockdown inhibited detection of free HIV-1 RNA 5′ ends at all time points. The difference in detection of free HIV-1 RNA 5′ ends in infected DBR1 knockdown versus control cells was eliminated by in vitro incubation of infected cell RNAs with yeast or human DBR1 enzyme prior to 5′ RACE and qRT-PCR. This was dependent on the 2′-5′ phosphatase activity of DBR1, since it did not occur when we used the catalytically inactive DBR1(N85A) mutant. Finally, HIV-1 RNA from infected DBR1 knockdown cells was resistant to RNase R that degrades linear RNAs but not RNAs in circular or lariat-like conformations. These results provide evidence for formation of a lariat-like structure involving the 5′ end of HIV-1 RNA during an early step in infection and the involvement of DBR1 in resolving it. IMPORTANCE Our findings support a new view of the early steps in HIV genome replication. We show that the HIV genomic RNA is rapidly decapped and forms a lariat-like structure after entering a cell. The lariat-like structure is subsequently resolved by the cellular enzyme DBR1, leaving a 5′ phosphate. This pathway is similar to the formation and resolution of pre-mRNA intron lariats and therefore suggests that similar mechanisms may be used by HIV. Our work therefore opens a new area of investigation in HIV replication and may ultimately uncover new targets for inhibiting HIV replication and for preventing the development of AIDS.

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Clark, Nathaniel, Adam Katolik, Allison J. Taggart, Luke Buerer, Stephen Holloway, Nathan Miller, John D. Phillips, Colin P. Farrell, Masad J. Damha, and William Fairbrother. "Metal content and kinetic properties of yeast RNA lariat debranching enzyme Dbr1." RNA, April 22, 2022, rna.079159.122. http://dx.doi.org/10.1261/rna.079159.122.

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In eucaryotic cells, intron lariats produced by the spliceosome contain a 2′5′ phosphodiester linkage. The RNA lariat debranching enzyme, Dbr1, is the only enzyme known to hydrolyze this bond. Dbr1 is a member of the metallophosphoesterase (MPE) family of enzymes, and recent X-ray crystal structures and biochemistry data demonstrate that Dbr1 from Entamoeba histolytica uses combinations of Mn2+, Zn2+, and Fe2+ as enzymatic co-factors. Here, we examine the kinetic properties and metal dependence of the Dbr1 homolog from Saccharomyces cerevisiae (yDbr1). Elemental analysis measured stoichiometric quantities of Fe and Zn in yDbr1 purified following heterologous expression E. coli. We analyzed the ability of Fe2+, Zn2+, and Mn2+ to reconstitute activity in metal-free apoenzyme. Purified yDbr1 was highly active, turning over substate at 5.6 sec-1, and apo-yDbr1 reconstituted with Fe2+ was the most active species, turning over at 9.2 sec-1. We treated a human lymphoblastoid cells with the iron-chelator deferoxamine and measured a two-fold increase in cellular lariats. These data suggest that Fe is an important biological co-factor for Dbr1 enzymes.

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Choi, Yejin, Hyun-Hee Lee, Jiyeun Park, Sieun Kim, Soyoung Choi, Heeji Moon, Jiyoung Shin, et al. "Intron turnover is essential to the development and pathogenicity of the plant pathogenic fungus Fusarium graminearum." Communications Biology 5, no. 1 (October 26, 2022). http://dx.doi.org/10.1038/s42003-022-04111-3.

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AbstractIntron lariats excised during the splicing process are rapidly degraded by RNA lariat debranching enzyme (Dbr1) and several exonucleases. Rapid turnover of lariat RNA is essential to cellular RNA homeostasis. However, the functions of Dbr1 have not been investigated in filamentous fungi. Here, we characterized the molecular functions of Dbr1 in Fusarium graminearum, a major fungal plant pathogen. Deletion of FgDBR1 resulted in pleiotropic defects in hyphal growth, conidiation, sexual reproduction, and virulence. Through transcriptome analysis, we revealed that the deletion mutant exhibited global accumulation of intron lariats and upregulation of ribosome-related genes. Excessive accumulation of lariat RNA led to reduced overall protein synthesis, causing various phenotypic defects in the absence of FgDBR1. The results of this study demonstrate that a compromised intron turnover process affects development and pathogenesis in this fungus and that Dbr1 function is critical to plant pathogenic fungi.

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Wu, Chengyun, Xiaoqing Wang, Weibo Zhen, Yaqing Nie, Yan Li, Penglai Yuan, Qiaoqiao Liu, et al. "SICKLE modulates lateral root development by promoting degradation of lariat intronic RNA." Plant Physiology, July 5, 2022. http://dx.doi.org/10.1093/plphys/kiac301.

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Abstract Plant lateral roots (LRs) play vital roles in anchorage and uptake of water and nutrients. Here, we reveal that degradation of lariat intronic RNAs (lariRNAs) modulated by SICKLE (SIC) is required for LR development in Arabidopsis (Arabidopsis thaliana). Loss of SIC results in hyper-accumulation of lariRNAs and restricts the outgrowth of LR primordia, thereby reducing the number of emerged LRs. Decreasing accumulation of lariRNAs by over-expressing RNA debranching enzyme 1 (DBR1), a rate-limiting enzyme of lariRNA decay, restored LR defects in SIC-deficient plants. Mechanistically, SIC interacts with DBR1 and facilitates its nuclear accumulation, which is achieved through two functionally redundant regions (SIC1–244 and SIC252–319) for nuclear localization. Of the remaining amino acids in this region, six (SIC245–251) comprise a DBR1-interacting region while two (SICM246 and SICW251) are essential for DBR1–SIC interaction. Reducing lariRNAs restored microRNA (miRNA) levels and LR development in lariRNA hyper-accumulating plants, suggesting that these well-known regulators of LR development mainly function downstream of lariRNAs. Taken together, we propose that SIC acts as an enhancer of DBR1 nuclear accumulation by driving nuclear localization through direct interaction, thereby promoting lariRNA decay to fine-tune miRNA biogenesis and modulating LR development.

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Li, Dongze, Xiaoli Chen, Fanghui Li, Yu Jia, Zhilin Li, Yi Liu, Lei Ye, et al. "Evaluation of risk stratification program based on trajectories of functional capacity in patients with acute coronary syndrome: The REACP study." Frontiers in Cardiovascular Medicine 9 (December 20, 2022). http://dx.doi.org/10.3389/fcvm.2022.1020488.

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BackgroundAs a validated assessment tool for functional disability (activities of daily living), the Barthel index (BI) assessed initially at admission has the potential to stratify patients with high-risk acute coronary syndrome (ACS). Dynamic trajectory evaluation of functional capacity in hospitals may provide more prognostic information. We aimed to establish a novel dynamic BI-based risk stratification program (DBRP) during hospitalization to predict outcomes among ACS patients.MethodsA total of 2,837 ACS patients were included from the Retrospective Multicenter Study for Early Evaluation of Acute Chest Pain. The DBRP rating (low, medium, and high-risk categories) was calculated from dynamic BI at admission and discharge. The primary outcome was all-cause mortality, and the secondary outcome was cardiac mortality.ResultsOf all the included patients, 312 (11%) died during a median follow-up period of 18.0 months. Kaplan–Meier analysis revealed that the cumulative mortality was significantly higher in patients in the higher risk category according to the DBRP. Multivariable Cox regression analysis indicated that, compared to the low-risk category, the higher risk category in the DBRP was an independent strong predictor of all-cause mortality after adjusting for confounding factors (medium-risk category: hazard ratio [HR]: 1.756, 95% confidence interval [95% CI]: 1.214–2.540; P = 0.003; high-risk category: HR: 5.052, 95% CI: 3.744–6.817; P < 0.001), and the same result was found for cardiac mortality.ConclusionThe DBRP was a useful risk stratification tool for the early dynamic assessment of patients with ACS.Clinical trial registration[http://www.chictr.org.cn], identifier [ChiCTR1900024657].

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Bogan, Richard K., Michael J. Thorpy, Yves Dauvilliers, Markku Partinen, Rafael Del Rio Villegas, Nancy Foldvary-Schaefer, Roman Skowronski, Lihua Tang, Franck Skobieranda, and Karel Šonka. "Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy." Sleep, October 14, 2020. http://dx.doi.org/10.1093/sleep/zsaa206.

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Abstract Study Objectives Evaluate efficacy and safety of lower-sodium oxybate (LXB), a novel oxybate medication with 92% less sodium than sodium oxybate (SXB). Methods Adults aged 18–70 years with narcolepsy with cataplexy were eligible. The study included a ≤30-day screening period; a 12-week, open-label, optimized treatment and titration period to transition to LXB from previous medications for the treatment of cataplexy; a 2-week stable-dose period (SDP); a 2-week, double-blind, randomized withdrawal period (DBRWP); and a 2-week safety follow-up. During DBRWP, participants were randomized 1:1 to placebo or to continue LXB treatment. Results Efficacy was assessed in 134 participants who received randomized treatment, and safety was assessed in all enrolled participants (N = 201). Statistically significant worsening of symptoms was observed in participants randomized to placebo, with median (first quartile [Q1], third quartile [Q3]) change in weekly number of cataplexy attacks from SDP to DBRWP (primary efficacy endpoint) in the placebo group of 2.35 (0.00, 11.61) versus 0.00 (−0.49, 1.75) in the LXB group (p < 0.0001; mean [standard deviation, SD] change: 11.46 [24.751] vs 0.12 [5.772]), and median (Q1, Q3) change in Epworth Sleepiness Scale score (key secondary efficacy endpoint) of 2.0 (0.0, 5.0) in the placebo group versus 0.0 (−1.0, 1.0) in the LXB group (p < 0.0001; mean [SD] change: 3.0 [4.68] vs 0.0 [2.90]). The most common treatment-emergent adverse events with LXB were headache (20.4%), nausea (12.9%), and dizziness (10.4%). Conclusions Efficacy of LXB for the treatment of cataplexy and excessive daytime sleepiness was demonstrated. The safety profile of LXB was consistent with SXB. Clinical trial registration NCT03030599.

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Valdés, Jesús, Carlos Ortuño-Pineda, Odila Saucedo-Cárdenas, and María S. Mendoza-Figueroa. "Unexplored Molecular Features of the Entamoeba histolytica RNA Lariat Debranching Enzyme Dbr1 Expression Profile." Frontiers in Cellular and Infection Microbiology 8 (July 4, 2018). http://dx.doi.org/10.3389/fcimb.2018.00228.

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Clark, Nathaniel E., Adam Katolik, Anastasia Welch, Christoph Schorl, Stephen P. Holloway, Jonathan P. Schuermann, P. John Hart, Alexander B. Taylor, Masad J. Damha, and William G. Fairbrother. "Crystal Structure of the RNA Lariat Debranching Enzyme Dbr1 with Hydrolyzed Phosphorothioate RNA Product." Biochemistry, December 9, 2022. http://dx.doi.org/10.1021/acs.biochem.2c00590.

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Zhang, Peng, Quentin Philippot, Weicheng Ren, Wei-Te Lei, Juan Li, Peter D. Stenson, Pere Soler Palacín, et al. "Genome-wide detection of human variants that disrupt intronic branchpoints." Proceedings of the National Academy of Sciences 119, no. 44 (October 28, 2022). http://dx.doi.org/10.1073/pnas.2211194119.

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Pre-messenger RNA splicing is initiated with the recognition of a single-nucleotide intronic branchpoint (BP) within a BP motif by spliceosome elements. Forty-eight rare variants in 43 human genes have been reported to alter splicing and cause disease by disrupting BP. However, until now, no computational approach was available to efficiently detect such variants in massively parallel sequencing data. We established a comprehensive human genome-wide BP database by integrating existing BP data and generating new BP data from RNA sequencing of lariat debranching enzyme DBR1-mutated patients and from machine-learning predictions. We characterized multiple features of BP in major and minor introns and found that BP and BP-2 (two nucleotides upstream of BP) positions exhibit a lower rate of variation in human populations and higher evolutionary conservation than the intronic background, while being comparable to the exonic background. We developed BPHunter as a genome-wide computational approach to systematically and efficiently detect intronic variants that may disrupt BP recognition. BPHunter retrospectively identified 40 of the 48 known pathogenic BP variants, in which we summarized a strategy for prioritizing BP variant candidates. The remaining eight variants all create AG-dinucleotides between the BP and acceptor site, which is the likely reason for missplicing. We demonstrated the practical utility of BPHunter prospectively by using it to identify a novel germline heterozygous BP variant of STAT2 in a patient with critical COVID-19 pneumonia and a novel somatic intronic 59-nucleotide deletion of ITPKB in a lymphoma patient, both of which were validated experimentally. BPHunter is publicly available from https://hgidsoft.rockefeller.edu/BPHunter and https://github.com/casanova-lab/BPHunter .

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Journal articles on the topic 'Dbr1p'

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