Abstract Background and aims In previous phase III studies, the PCSK9 monoclonal antibody alirocumab was administered at doses of 75 or 150 mg every 2 weeks (Q2W). CHOICE I (NCT01926782) evaluated ...300 mg every 4 weeks (Q4W) in patients on either maximally tolerated statin or no statin, both ± other lipid-lowering therapies. Methods CHOICE I included patients with hypercholesterolemia at moderate-to-very-high cardiovascular risk. Patients were randomized to alirocumab 300 mg Q4W, 75 mg Q2W (calibrator arm), or placebo for 48 weeks, with dose adjustment for either alirocumab arm to 150 mg Q2W at Week (W) 12 if at W8 LDL-C levels were >70/100 mg/dL (1.8/2.6 mmol/L) depending on cardiovascular risk or LDL-C reduction was <30% from baseline. Co-primary endpoints were percent LDL-C change from baseline to W24, and to time-averaged LDL-C over W21–24. Results Approximately two-thirds of randomized patients were receiving statins. At W12, 14.7% (no statin) and 19.3% (statin) of patients receiving alirocumab 300 mg Q4W required dose adjustment. At W24, significant LDL-C reductions from baseline were observed with alirocumab 300 mg Q4W: mean differences were −52.7% (no statin; placebo: –0.3%) and −58.8% (statin; placebo: –0.1%). Average LDL-C reductions from baseline to W21–24 were also significantly greater with alirocumab 300 mg Q4W vs. placebo in patients not receiving (−56.9% vs. –1.6%) and receiving statin (−65.8% vs. –0.8%). Treatment-emergent adverse event rates ranged from 61.1 to 75.0% (placebo) and 71.5 to 78.1% (alirocumab 300 mg Q4W). Conclusions Alirocumab 300 mg Q4W is a viable additional treatment option in patients requiring LDL-C-lowering.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
The Ccr4-Not complex controls RNA polymerase II (Pol II) dependent gene expression and proteasome function. The Not4 ubiquitin ligase is a Ccr4-Not subunit that has both a RING domain and a conserved ...RNA recognition motif and C3H1 domain (referred to as the RRM-C domain) with unknown function. We demonstrate that while individual Not4 RING or RRM-C mutants fail to replicate the proteasomal defects found in Not4 deficient cells, mutation of both exhibits a Not4 loss of function phenotype. Transcriptome analysis revealed that the Not4 RRM-C affects a specific subset of Pol II-regulated genes, including those involved in transcription elongation, cyclin-dependent kinase regulated nutrient responses, and ribosomal biogenesis. The Not4 RING, RRM-C, or RING/RRM-C mutations cause a generalized increase in Pol II binding at a subset of these genes, yet their impact on gene expression does not always correlate with Pol II recruitment which suggests Not4 regulates their expression through additional mechanisms. Intriguingly, we find that while the Not4 RRM-C is dispensable for Ccr4-Not association with RNA Pol II, the Not4 RING domain is required for these interactions. Collectively, these data elucidate previously unknown roles for the conserved Not4 RRM-C and RING domains in regulating Ccr4-Not dependent functions in vivo.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The Metaverse has been the centre of attraction for educationists for quite some time. This field got renewed interest with the announcement of social media giant Facebook as it rebranding and ...positioning it as Meta. While several studies conducted literature reviews to summarize the findings related to the Metaverse in general, no study to the best of our knowledge focused on systematically summarizing the finding related to the Metaverse in education. To cover this gap, this study conducts a systematic literature review of the Metaverse in education. It then applies both content and bibliometric analysis to reveal the research trends, focus, and limitations of this research topic. The obtained findings reveal the research gap in lifelogging applications in educational Metaverse. The findings also show that the design of Metaverse in education has evolved over generations, where generation Z is more targeted with artificial intelligence technologies compared to generation X or Y. In terms of learning scenarios, there have been very few studies focusing on mobile learning, hybrid learning, and micro learning. Additionally, no study focused on using the Metaverse in education for students with disabilities. The findings of this study provide a roadmap of future research directions to be taken into consideration and investigated to enhance the adoption of the Metaverse in education worldwide, as well as to enhance the learning and teaching experiences in the Metaverse.
Intravascular red cell hemolysis impairs nitric oxide (NO)-redox homeostasis, producing endothelial dysfunction, platelet activation, and vasculopathy. Red blood cell storage under standard ...conditions results in reduced integrity of the erythrocyte membrane, with formation of exocytic microvesicles or microparticles and hemolysis, which we hypothesized could impair vascular function and contribute to the putative storage lesion of banked blood.
We now find that storage of human red blood cells under standard blood banking conditions results in the accumulation of cell-free and microparticle-encapsulated hemoglobin, which, despite 39 days of storage, remains in the reduced ferrous oxyhemoglobin redox state and stoichiometrically reacts with and scavenges the vasodilator NO. Using stopped-flow spectroscopy and laser-triggered NO release from a caged NO compound, we found that both free hemoglobin and microparticles react with NO about 1000 times faster than with intact erythrocytes. In complementary in vivo studies, we show that hemoglobin, even at concentrations below 10 μmol/L (in heme), produces potent vasoconstriction when infused into the rat circulation, whereas controlled infusions of methemoglobin and cyanomethemoglobin, which do not consume NO, have substantially reduced vasoconstrictor effects. Infusion of the plasma from stored human red blood cell units into the rat circulation produces significant vasoconstriction related to the magnitude of storage-related hemolysis.
The results of these studies suggest new mechanisms for endothelial injury and impaired vascular function associated with the most fundamental of storage lesions, hemolysis.
ABSTRACT
To understand and engineer plant metabolism, we need a comprehensive and accurate annotation of all metabolic information across plant species. As a step towards this goal, we generated ...genome‐scale metabolic pathway databases of 126 algal and plant genomes, ranging from model organisms to crops to medicinal plants (https://plantcyc.org). Of these, 104 have not been reported before. We systematically evaluated the quality of the databases, which revealed that our semi‐automated validation pipeline dramatically improves the quality. We then compared the metabolic content across the 126 organisms using multiple correspondence analysis and found that Brassicaceae, Poaceae, and Chlorophyta appeared as metabolically distinct groups. To demonstrate the utility of this resource, we used recently published sorghum transcriptomics data to discover previously unreported trends of metabolism underlying drought tolerance. We also used single‐cell transcriptomics data from the Arabidopsis root to infer cell type‐specific metabolic pathways. This work shows the quality and quantity of our resource and demonstrates its wide‐ranging utility in integrating metabolism with other areas of plant biology.
Plant Metabolic Network 15 is a comprehensive resource containing high‐quality metabolic enzyme, reaction, and pathway annotations for 126 plant and algal genomes and demonstrated application for interpreting omics data.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
IMPORTANCE: Understanding adverse effects of contemporary treatment approaches for men with favorable-risk and unfavorable-risk localized prostate cancer could inform treatment selection. OBJECTIVE: ...To compare functional outcomes associated with prostate cancer treatments over 5 years after treatment. DESIGN, SETTING, AND PARTICIPANTS: Prospective, population-based cohort study of 1386 men with favorable-risk (clinical stage cT1 to cT2bN0M0, prostate-specific antigen PSA ≤20 ng/mL, and Grade Group 1-2) prostate cancer and 619 men with unfavorable-risk (clinical stage cT2cN0M0, PSA of 20-50 ng/mL, or Grade Group 3-5) prostate cancer diagnosed in 2011 through 2012, accrued from 5 Surveillance, Epidemiology and End Results Program sites and a US prostate cancer registry, with surveys through September 2017. EXPOSURES: Treatment with active surveillance (n = 363), nerve-sparing prostatectomy (n = 675), external beam radiation therapy (EBRT; n = 261), or low-dose-rate brachytherapy (n = 87) for men with favorable-risk disease and treatment with prostatectomy (n = 402) or EBRT with androgen deprivation therapy (n = 217) for men with unfavorable-risk disease. MAIN OUTCOMES AND MEASURES: Patient-reported function, based on the 26-item Expanded Prostate Index Composite (range, 0-100), 5 years after treatment. Regression models were adjusted for baseline function and patient and tumor characteristics. Minimum clinically important difference was 10 to 12 for sexual function, 6 to 9 for urinary incontinence, 5 to 7 for urinary irritative symptoms, and 4 to 6 for bowel and hormonal function. RESULTS: A total of 2005 men met inclusion criteria and completed the baseline and at least 1 postbaseline survey (median interquartile range age, 64 59-70 years; 1529 of 1993 participants 77% were non-Hispanic white). For men with favorable-risk prostate cancer, nerve-sparing prostatectomy was associated with worse urinary incontinence at 5 years (adjusted mean difference, −10.9 95% CI, −14.2 to −7.6) and sexual function at 3 years (adjusted mean difference, −15.2 95% CI, −18.8 to −11.5) compared with active surveillance. Low-dose-rate brachytherapy was associated with worse urinary irritative (adjusted mean difference, −7.0 95% CI, −10.1 to −3.9), sexual (adjusted mean difference, −10.1 95% CI, −14.6 to −5.7), and bowel (adjusted mean difference, −5.0 95% CI, −7.6 to −2.4) function at 1 year compared with active surveillance. EBRT was associated with urinary, sexual, and bowel function changes not clinically different from active surveillance at any time point through 5 years. For men with unfavorable-risk disease, EBRT with ADT was associated with lower hormonal function at 6 months (adjusted mean difference, −5.3 95% CI, −8.2 to −2.4) and bowel function at 1 year (adjusted mean difference, −4.1 95% CI, −6.3 to −1.9), but better sexual function at 5 years (adjusted mean difference, 12.5 95% CI, 6.2-18.7) and incontinence at each time point through 5 years (adjusted mean difference, 23.2 95% CI, 17.7-28.7), than prostatectomy. CONCLUSIONS AND RELEVANCE: In this cohort of men with localized prostate cancer, most functional differences associated with contemporary management options attenuated by 5 years. However, men undergoing prostatectomy reported clinically meaningful worse incontinence through 5 years compared with all other options, and men undergoing prostatectomy for unfavorable-risk disease reported worse sexual function at 5 years compared with men who underwent EBRT with ADT.
Protein function is regulated by diverse posttranslational modifications. The mitochondrial sirtuin SIRT5 removes malonyl and succinyl moieties from target lysines. The spectrum of protein substrates ...subject to these modifications is unknown. We report systematic profiling of the mammalian succinylome, identifying 2,565 succinylation sites on 779 proteins. Most of these do not overlap with acetylation sites, suggesting differential regulation of succinylation and acetylation. Our analysis reveals potential impacts of lysine succinylation on enzymes involved in mitochondrial metabolism; e.g., amino acid degradation, the tricarboxylic acid cycle (TCA) cycle, and fatty acid metabolism. Lysine succinylation is also present on cytosolic and nuclear proteins; indeed, we show that a substantial fraction of SIRT5 is extramitochondrial. SIRT5 represses biochemical activity of, and cellular respiration through, two protein complexes identified in our analysis, pyruvate dehydrogenase complex and succinate dehydrogenase. Our data reveal widespread roles for lysine succinylation in regulating metabolism and potentially other cellular functions.
•Lysine succinylation is a posttranslational modification regulated by SIRT5•We profile lysine succinylation in mammalian fibroblasts and liver tissue•Succinylation is present on diverse mitochondrial and nonmitochondrial proteins•SIRT5 suppresses pyruvate dehydrogenase complex and succinate dehydrogenase
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pontocerebellar hypoplasia (PCH) is a group of rare neurodevelopmental disorders with limited diagnostic and therapeutic options. Mutations in WDR11, a subunit of the FAM91A1 complex, have been found ...in patients with PCH-like symptoms; however, definitive evidence that the mutations are causal is still lacking. Here, we show that depletion of FAM91A1 results in developmental defects in zebrafish similar to that of TBC1D23, an established PCH gene. FAM91A1 and TBC1D23 directly interact with each other and cooperate to regulate endosome-to-Golgi trafficking of KIAA0319L, a protein known to regulate axonal growth. Crystal structure of the FAM91A1-TBC1D23 complex reveals that TBC1D23 binds to a conserved surface on FAM91A1 by assuming a Z-shaped conformation. More importantly, the interaction between FAM91A1 and TBC1D23 can be used to predict the risk of certain TBC1D23-associated mutations to PCH. Collectively, our study provides a molecular basis for the interaction between TBC1D23 and FAM91A1 and suggests that disrupted endosomal trafficking underlies multiple PCH subtypes.
Phytoplankton blooms in coastal oceans can be beneficial to coastal fisheries production and ecosystem function, but can also cause major environmental problems
-yet detailed characterizations of ...bloom incidence and distribution are not available worldwide. Here we map daily marine coastal algal blooms between 2003 and 2020 using global satellite observations at 1-km spatial resolution. We found that algal blooms occurred in 126 out of the 153 coastal countries examined. Globally, the spatial extent (+13.2%) and frequency (+59.2%) of blooms increased significantly (P < 0.05) over the study period, whereas blooms weakened in tropical and subtropical areas of the Northern Hemisphere. We documented the relationship between the bloom trends and ocean circulation, and identified the stimulatory effects of recent increases in sea surface temperature. Our compilation of daily mapped coastal phytoplankton blooms provides the basis for global assessments of bloom risks and benefits, and for the formulation or evaluation of management or policy actions.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
An on-demand anesthetic that would only take effect when needed and where the intensity of anesthesia could be easily adjustable according to patients' needs would be highly desirable. Here, we ...design and synthesize a macromolecular prodrug (P407-CM-T) in which the local anesthetic tetracaine (T) is attached to the polymer poloxamer 407 (P407) via a photo-cleavable coumarin linkage (CM). P407-CM-T solution is an injectable liquid at room temperature and gels near body temperature. The macromolecular prodrug has no anesthetic effect itself unless irradiated with a low-power blue light emitting diode (LED), resulting in local anesthesia. By adjusting the intensity and duration of irradiation, the anesthetic effect can be modulated. Local anesthesia can be repeatedly triggered.
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