MicroRNA (miRNA) maturation is initiated by Microprocessor composed of RNase III DROSHA and its cofactor DGCR8, whose fidelity is critical for generation of functional miRNAs. To understand how ...Microprocessor recognizes pri-miRNAs, we here reconstitute human Microprocessor with purified recombinant proteins. We find that Microprocessor is an ∼364 kDa heterotrimeric complex of one DROSHA and two DGCR8 molecules. Together with a 23-amino acid peptide from DGCR8, DROSHA constitutes a minimal functional core. DROSHA serves as a “ruler” by measuring 11 bp from the basal ssRNA-dsRNA junction. DGCR8 interacts with the stem and apical elements through its dsRNA-binding domains and RNA-binding heme domain, respectively, allowing efficient and accurate processing. DROSHA and DGCR8, respectively, recognize the basal UG and apical UGU motifs, which ensure proper orientation of the complex. These findings clarify controversies over the action mechanism of DROSHA and allow us to build a general model for pri-miRNA processing.
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•Microprocessor is a trimeric complex with one DROSHA and two DGCR8•Functional core of Microprocessor contains DROSHA and the C-terminal tail of DGCR8•DROSHA serves as a ruler by recognizing the basal elements•DGCR8 interacts with the apical elements to ensure fidelity of processing
Functional reconstruction of human Microprocessor defines its molecular stoichiometry and the specific role of each component in substrate recognition and orientation, revealing a comprehensive processing mechanism of Microprocessor.
Even though it is widely known that mechanical properties of papers are dependent upon fiber morphology such as fiber length and cell wall thickness, existing macroscopic models are limited in ...describing the microscopic traits of pulp. Thus, we proposed a multiscale model by integrating a macroscopic model (i.e., Purdue model) and a microscopic model (i.e., kinetic Monte Carlo algorithm) to capture the dynamic evolution of the fiber morphology as well as conventional pulp quality index such as Kappa number. Then, a reduced‐order model is identified to handle the computational requirement of the multiscale model, and implemented to a model‐based controller to regulate both the fiber length and the Kappa number which are expressed in the forms of conflicting objective functions. The epsilon‐constraint method is employed to find the Pareto optimal sets to provide decision makers with the degree of freedom to choose one according to their preferred end‐use paper properties.
Structure of Human DROSHA Kwon, S. Chul; Nguyen, Tuan Anh; Choi, Yeon-Gil ...
Cell,
01/2016, Letnik:
164, Številka:
1-2
Journal Article
Recenzirano
Odprti dostop
MicroRNA maturation is initiated by RNase III DROSHA that cleaves the stem loop of primary microRNA. DROSHA functions together with its cofactor DGCR8 in a heterotrimeric complex known as ...Microprocessor. Here, we report the X-ray structure of DROSHA in complex with the C-terminal helix of DGCR8. We find that DROSHA contains two DGCR8-binding sites, one on each RNase III domain (RIIID), which mediate the assembly of Microprocessor. The overall structure of DROSHA is surprisingly similar to that of Dicer despite no sequence homology apart from the C-terminal part, suggesting that DROSHA may have evolved from a Dicer homolog. DROSHA exhibits unique features, including non-canonical zinc-finger motifs, a long insertion in the first RIIID, and the kinked link between Connector helix and RIIID, which explains the 11-bp-measuring “ruler” activity of DROSHA. Our study implicates the evolutionary origin of DROSHA and elucidates the molecular basis of Microprocessor assembly and primary microRNA processing.
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•The atomic structure of human DROSHA is solved at 3.2 Å resolution•Two DGCR8-binding sites on DROSHA mediate heterotrimeric Microprocessor assembly•Structural similarity of DROSHA to Dicer suggests its evolutionary origin•DROSHA-specific features account for the 11-bp measurement mechanism
The heretofore-elusive structure of DROSHA provides insights into how nascent microRNAs are recognized and cleaved in their initial processing step and reveals an unexpected similarity between DROSHA and DICER, the enzyme responsible for the second step of miRNA processing.
To investigate the characteristics and prevalence of poststroke depression (PSD) and poststroke emotional incontinence (PSEI) and the factors related to these conditions at admission and 3 months ...after stroke.
We evaluated 508 consecutive patients with acute ischemic stroke for PSD and PSEI at admission and 3 months later. PSD was evaluated using the Beck Depression Inventory, and PSEI was evaluated using Kim's criteria. Blood samples were collected and genotyped for the promoter region of the serotonin transporter protein (5-HTTLPR) and the number of tandem repeats within intron 2 (STin2 VNTR). Perceived social support (the ENRICHD Social Support Inventory) was also measured.
PSD and PSEI were present in 13.7% and 9.4% of patients, respectively, at admission and in 17.7% and 11.7%, respectively, at 3 months after stroke. Multivariate analyses showed that PSD at admission was associated with the NIH Stroke Scale score at admission (p < 0.001), whereas PSD at 3 months was associated with the presence of microbleeds (p < 0.01) and perceived low social support (p < 0.001). In contrast, only lesion location (p = 0.022) was associated with PSEI at admission, whereas modified Rankin Scale score (p = 0.019), STin2 VNTR (p = 0.040), and low social support (p = 0.042) were related to PSEI 3 months after stroke.
Diverse factors such as neurologic dysfunction, lesion location, microbleeds, genetic traits, and social support are differently related to acute and subacute emotional disturbances. Strategies to prevent or manage these problems should consider these differences.
Microprocessor, composed of DROSHA and its cofactor DGCR8, initiates microRNA (miRNA) biogenesis by processing the primary transcripts of miRNA (pri-miRNAs). Here we investigate the mechanism by ...which Microprocessor selects the cleavage site with single-nucleotide precision, which is crucial for the specificity and functionality of miRNAs. By testing ∼40,000 pri-miRNA variants, we find that for some pri-miRNAs the cleavage site is dictated mainly by the mGHG motif embedded in the lower stem region of pri-miRNA. Structural modeling and deep-sequencing-based complementation experiments show that the double-stranded RNA-binding domain (dsRBD) of DROSHA recognizes mGHG to place the catalytic center in the appropriate position. The mGHG motif as well as the mGHG-recognizing residues in DROSHA dsRBD are conserved across eumetazoans, suggesting that this mechanism emerged in an early ancestor of the animal lineage. Our findings provide a basis for the understanding of miRNA biogenesis and rational design of accurate small-RNA-based gene silencing.
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•The mGHG motif can dictate the cleavage site with single-nucleotide precision•Processing site of primary microRNA is determined by DROSHA rather than DGCR8•The dsRBD of DROSHA recognizes the mGHG motif
Target specificity of microRNA is determined by DROSHA cleavage sites. Kwon et al. show how DROSHA precisely selects the cleavage sites using the interaction between its double-stranded RNA-binding domain (dsRBD) and the mGHG motif of the primary microRNA.
The planar spin glass pattern is widely known for its inherent randomness, resulting from the geometrical frustration. As such, developing physical unclonable functions (PUFs)—which operate with ...device randomness—with planar spin glass patterns is a promising candidate for an advanced security systems in the upcoming digitalized society. Despite their inherent randomness, traditional magnetic spin glass patterns pose considerable obstacles in detection, making it challenging to achieve authentication in security systems. This necessitates the development of facilely observable mimetic patterns with similar randomness to overcome these challenges. Here, a straightforward approach is introduced using a topologically protected maze pattern in the chiral liquid crystals (LCs). This maze exhibits a comparable level of randomness to magnetic spin glass and can be reliably identified through the combination of optical microscopy with machine learning‐based object detection techniques. The “information” embedded in the maze can be reconstructed through thermal phase transitions of the LCs in tens of seconds. Furthermore, incorporating various elements can enhance the optical PUF, resulting in a multi‐factor security medium. It is expected that this security medium, based on microscopically controlled and macroscopically uncontrolled topologically protected structures, may be utilized as a next‐generation security system.
The deterministic and non‐deterministic properties of a topologically protected maze in the chiral liquid crystal (LC) resulting from microscopic order and macroscopic disorder accomplish a security system that serves as advanced artificial fingerprints. This system enables facile authentication through deep‐learning technology and can reconstruct information through the phase transition of LCs.
Novel SnO2−In2O3 heterostructured nanowires were produced via a thermal evaporation method, and their possible nucleation/growth mechanism is proposed. We found that the electronic conductivity of ...the individual SnO2−In2O3 nanowires was 2 orders of magnitude better than that of the pure SnO2 nanowires, due to the formation of Sn-doped In2O3 caused by the incorporation of Sn into the In2O3 lattice during the nucleation and growth of the In2O3 shell nanostructures. This provides the SnO2−In2O3 nanowires with an outstanding lithium storage capacity, making them suitable for promising Li ion battery electrodes.
Currently, the characteristics of carotid plaques are considered important factors for identifying subjects at high risk of stroke. This study aimed to test the hypothesis that carotid plaque ...composition assessed by CTA is associated with an increased risk of future major adverse cardiovascular events among asymptomatic subjects with moderate-to-severe carotid artery stenosis.
This single-center, retrospective cohort study included 194 carotid plaques from 176 asymptomatic subjects with moderate-to-severe carotid artery stenosis. The association of CTA-determined plaque composition with the risk of subsequent adverse cardiovascular events was analyzed.
During a median follow-up of 41 months, the adverse cardiovascular event incidence among 194 carotid plaques was 19.6%. There were significant differences in plaque Hounsfield units (
< .001) and spotty calcium presence (
< .001) between carotid plaques from subjects with and without subsequent adverse cardiovascular events. Multivariable analysis revealed carotid plaque Hounsfield unit density (
< .001) and spotty calcium (
< .001) as independent predictors of subsequent adverse cardiovascular events. In association with moderate carotid artery stenosis, the plaque Hounsfield unit values were significantly lower among carotid plaques from subjects who experienced subsequent adverse cardiovascular events (
= .002), strokes (
= .01), and cardiovascular deaths (
= .04); the presence of spotty calcium was significantly associated with the occurrence of adverse cardiovascular events (
= .001), acute coronary syndrome (
= .01), and cardiovascular death (
= .04).
Carotid plaque Hounsfield unit density and spotty calcium were independent predictors of a greater risk of adverse cardiovascular event occurrence.
Background and Purpose
Pain is common in post‐stroke patients and has been shown to be associated with depression, fatigue, and decreased quality of life (QOL). However, studies examining different ...types of post‐stroke pain are scarce. We investigated differences in the related factors and their QOL impacts between musculoskeletal pain (MSP) and central post‐stroke pain (CPSP).
Methods
We assessed 364 consecutive stroke patients who were admitted to Asan Medical Center and contacted 12 months after stroke onset. We categorized pain and paresthesia as MSP, CPSP, combined pain, or other pain. Post‐stroke depression (Beck Depression Inventory), fatigue (Fatigue Severity Scale), sleep disturbance (Verran Snyder‐Halpern scale), social support (ENRICHED Social Support Instrument), and QOL (Medical Outcome Study 36‐Item Short Form) were assessed.
Results
Of the 364 patients analyzed, 135 (37.1%) had pain, 78 (21.4%) had MSP, 22 (6.0%) had CPSP, 16 (4.4%) had combined pain, and 19 (5.2%) had other pain. In multivariate analyses, CPSP was related to modified Rankin scale (P=.004), sensory dysfunction (P<.001), thalamus lesion (P=.001), medulla lesion (P=.007), and fatigue (P=.026). MSP was related to motor dysfunction (P<.001) and fatigue (P=.003). QOL varied among groups with different types of pain (P<.001) and was the poorest in patients with combined pain.
Conclusions
Pain is common 12 months post‐stroke. The factors associated with CPSP and MSP differ, but are both closely associated with fatigue rather than depression. QOL is the poorest in patients with combined pain. Management of pain and fatigue may be important for improving the QOL in stroke patients.
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