Posttranscriptional modifications in transfer RNA (tRNA) are often critical for normal development because they adapt protein synthesis rates to a dynamically changing microenvironment. However, the ...precise cellular mechanisms linking the extrinsic stimulus to the intrinsic RNA modification pathways remain largely unclear. Here, we identified the cytosine-5 RNA methyltransferase NSUN2 as a sensor for external stress stimuli. Exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Using metabolic profiling, we showed that loss of tRNA methylation captured cells in a distinct catabolic state. Mechanistically, loss of NSUN2 altered the biogenesis of tRNA-derived noncoding fragments (tRFs) in response to stress, leading to impaired regulation of protein synthesis. The intracellular accumulation of a specific subset of tRFs correlated with the dynamic repression of global protein synthesis. Finally, NSUN2-driven RNA methylation was functionally required to adapt cell cycle progression to the early stress response. In summary, we revealed that changes in tRNA methylation profiles were sufficient to specify cellular metabolic states and efficiently adapt protein synthesis rates to cell stress.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chemogenetics revealed Gomez, Juan L.; Bonaventura, Jordi; Lesniak, Wojciech ...
Science,
08/2017, Letnik:
357, Številka:
6350
Journal Article
Recenzirano
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The chemogenetic technology DREADD (designer receptors exclusively activated by designer drugs) is widely used for remote manipulation of neuronal activity in freely moving animals. DREADD technology ...posits the use of “designer receptors,” which are exclusively activated by the “designer drug” clozapine N-oxide (CNO). Nevertheless, the in vivo mechanism of action of CNO at DREADDs has never been confirmed. CNO does not enter the brain after systemic drug injections and shows low affinity for DREADDs. Clozapine, to which CNO rapidly converts in vivo, shows high DREADD affinity and potency. Upon systemic CNO injections, converted clozapine readily enters the brain and occupies central nervous system–expressed DREADDs, whereas systemic subthreshold clozapine injections induce preferential DREADD-mediated behaviors.
Existing high-throughput methods to identify RNA-binding proteins (RBPs) are based on capture of polyadenylated RNAs and cannot recover proteins that interact with nonadenylated RNAs, including long ...noncoding RNA, pre-mRNAs and bacterial RNAs. We present orthogonal organic phase separation (OOPS), which does not require molecular tagging or capture of polyadenylated RNA, and apply it to recover cross-linked protein-RNA and free protein, or protein-bound RNA and free RNA, in an unbiased way. We validated OOPS in HEK293, U2OS and MCF10A human cell lines, and show that 96% of proteins recovered were bound to RNA. We show that all long RNAs can be cross-linked to proteins, and recovered 1,838 RBPs, including 926 putative novel RBPs. OOPS is approximately 100-fold more efficient than existing methods and can enable analyses of dynamic RNA-protein interactions. We also characterize dynamic changes in RNA-protein interactions in mammalian cells following nocodazole arrest, and present a bacterial RNA-interactome for Escherichia coli. OOPS is compatible with downstream proteomics and RNA sequencing, and can be applied in any organism.
Background In response to reports of thrombosis with thrombocytopenia syndrome (TTS) post-vaccination, the Johnson & Johnson (J&J) vaccine was paused and then restarted in April 2021. Our objective ...was to assess whether this pause adversely impacted vaccine confidence. Methods Two large internet-based surveys were conducted in the US among adults to measure knowledge, attitudes and perceptions of the J&J vaccine pause and rates of vaccine hesitancy among unvaccinated persons before, during and after the pause. Results Among 66% of respondents aware of the pause, 44% identified blood clots as the reason for the pause without prompting. The impact of the pause on vaccine behavior among unvaccinated persons and perception of the vaccine safety system was mixed and modified by trust in the public health authorities. Those who were less willing to get vaccinated because of the pause were less inclined for all vaccines, not only the J&J product. Moreover, a notable proportion (22.1%) of the small number of persons (n = 30) vaccinated with the J&J vaccine after the pause reported not receiving information about the risk of TTS. The proportion of unvaccinated persons who were hesitant was increasing before and during the pause and then leveled off after the pause. Conclusions The J&J vaccine pause is unlikely to be a major barrier to vaccine uptake. Public attitudes about vaccines may be more resilient than appreciated, especially when safety issues are investigated with transparent communication. This paper has important implications for messaging and program administration with future vaccine-specific adverse events. Efforts may be warranted to ensure all persons being offered the J&J vaccine are made aware of the risk of TTS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
High-resolution Airborne Wide-band Camera (HAWC
+
) is the facility far-infrared imager and polarimeter for SOFIA, NASA’s Stratospheric Observatory for Infrared Astronomy. It is designed to cover the ...portion of the infrared spectrum that is completely inaccessible to ground-based observatories and which is essential for studies of astronomical sources with temperatures between tens and hundreds of degrees Kelvin. Its ability to make polarimetric measurements of aligned dust grains provides a unique new capability for studying interstellar magnetic fields. HAWC
+
began commissioning flights in April 2016 and was accepted as a facility instrument in early 2018. In this paper, we describe the instrument, its operational procedures, and its performance on the observatory.
Einstein et al. (2021) uncover a novel role for the RNA-binding protein YTHDF2, one of the m
A reader proteins, in TNBC proliferation and survival. This study demonstrates the clinical potential of ...targeting a specific reader protein in the treatment of breast cancer.
During the translation surveillance mechanism known as ribosome-associated quality control, the ASC-1 complex (ASCC) disassembles ribosomes stalled on the mRNA. Here, we show that there are two ...distinct classes of stalled ribosome. Ribosomes stalled by translation elongation inhibitors or methylated mRNA are short lived in human cells because they are split by the ASCC. In contrast, although ultraviolet light and 4-nitroquinoline 1-oxide induce ribosome stalling by damaging mRNA, and the ASCC is recruited to these stalled ribosomes, we found that they are refractory to the ASCC. Consequently, unresolved UV- and 4NQO-stalled ribosomes persist in human cells. We show that ribosome stalling activates cell-cycle arrest, partly through ZAK-p38MAPK signaling, and that this cell-cycle delay is prolonged when the ASCC cannot resolve stalled ribosomes. Thus, we propose that the sensitivity of stalled ribosomes to the ASCC influences the kinetics of stall resolution, which in turn controls the adaptive stress response.
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•The ASCC splits many types of stalled ribosome, but some are refractory to the ASCC•ASCC-resistant stalled ribosomes are caused by bulky adduct damage within the mRNA•Failure of ASCC to resolve stalled ribosomes promotes a prolonged cell-cycle arrest•Unresolved stalled ribosomes activate ZAK/p38MAPK signaling leading to G2 arrest
Stoneley et al. reveal that although the ribosome splitting activity of the ASCC resolves many ribosomes stalled during translation, ribosomes stalled by bulky nucleobase mRNA modifications are refractory to the ASCC. ASCC-resistant stalled ribosomes are long lived in the cell and stimulate prolonged cell-cycle arrest through the ZAK/p38MAPK signaling axis.
In tumourigenesis, oncogenes or dysregulated tumour suppressor genes alter the canonical translation machinery leading to a reprogramming of the translatome that, in turn, promotes the translation of ...selected mRNAs encoding proteins involved in proliferation and metastasis. It is therefore unsurprising that abnormal expression levels and activities of eukaryotic initiation factors (eIFs), elongation factors (eEFs) or termination factors (eRFs) are associated with poor outcome for patients with a wide range of cancers. In this review we discuss how RNA binding proteins (RBPs) within the canonical translation factor machinery are dysregulated in cancers and how targeting such proteins is leading to new therapeutic avenues.
Third Universal Definition of Myocardial Infarction Thygesen, Kristian; Alpert, Joseph S; Jaffe, Allan S ...
Journal of the American College of Cardiology,
10/2012, Letnik:
60, Številka:
16
Journal Article, Conference Proceeding, Web Resource
Recenzirano
Odprti dostop
.1595 Abbreviations and acronyms ACCF = American College of Cardiology Foundation ACS = acute coronary syndrome AHA = American Heart Association CAD = coronary artery disease CABG = coronary artery ...bypass grafting CKMB = creatine kinase MB isoform cTn = cardiac troponin CT = computed tomography CV = coefficient of variation ECG = electrocardiogram ESC = European Society of Cardiology FDG = fluorodeoxyglucose h = hour(s) HF = heart failure LBBB = left bundle branch block LV = left ventricle LVH = left ventricular hypertrophy MI = myocardial infarction mlBG = meta-iodo-benzylguanidine min = minute(s) MONICA = Multinational MONItoring of trends and determinants in CArdiovascular disease MPS = myocardial perfusion scintigraphy MRI = magnetic resonance imaging mV = millivolt(s) ng/L = nanogram(s) per liter Non-Q Ml = non-Q wave myocardial infarction NSTEMI = non-ST-elevation myocardial infarction PCI = percutaneous coronary intervention PET = positron emission tomography pg/mL = pictogram(s) per milliliter Q wave Ml = Q wave myocardial infarction RBBB = right bundle branch block sec = second(s) SPECT = single photon emission computed tomography STEMI = ST elevation myocardial infarction ST-T = ST-segment -T wave URL = upper reference limit WHF = World Heart Federation WHO = World Health Organization Introduction Myocardial infarction (MI) can be recognized by clinical features, including electrocardiographic (ECG) findings, elevated values of biochemical markers (biomarkers) of myocardial necrosis, and by imaging, or may be defined by pathology. Additionally, the management of patients with MI has significantly improved, resulting in less myocardial injury and necrosis, in spite of a similar clinical presentation. ...it appears necessary to distinguish the various conditions which may cause MI, such as 'spontaneous' and 'procedure-related' MI. ...physicians, other healthcare providers and patients require an up-to-date definition of MI.
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