South Korea introduced mandatory social health insurance for industrial workers in large corporations in 1977, and extended it incrementally to the self-employed until it covered the entire ...population in 1989. Thirty years of national health insurance in Korea can provide valuable lessons on key issues in health care financing policy which now face many low- and middle-income countries aiming to achieve universal health care coverage, such as: tax versus social health insurance; population and benefit coverage; single scheme versus multiple schemes; purchasing and provider payment method; and the role of politics and political commitment. National health insurance in Korea has been successful in mobilizing resources for health care, rapidly extending population coverage, effectively pooling public and private resources to purchase health care for the entire population, and containing health care expenditure. However, there are also challenges posed by the dominance of private providers paid by fee-for-service, the rapid aging of the population, and the public-private mix related to private health insurance.
Antimicrobial activity of the 18 prenylated flavonoids, which were purified from five different medicinal plants, was evaluated by determination of MIC using the broth microdilution methods against ...four bacterial and two fungal microorganisms (Candida albicans, Saccaromyces cerevisiae, Escherichia coli, Salmonella typhimurium, Staphylococcus epidermis and S. aureus). Papyriflavonol A, kuraridin, sophoraflavanone D and sophoraisoflavanone A exhibited a good antifungal activity with strong antibacterial activity. Kuwanon C, mulberrofuran G, albanol B, kenusanone A and sophoraflavanone G showed strong antibacterial activity with 5–30μg/ml of MICs. Morusin, sanggenon B and D, kazinol B, kurarinone, kenusanone C and isosophoranone were effective to only gram positive bacteria, and broussochalcone A was effective to C. albicans. IC50 values of papyriflavonol A, kuraridin, sophoraflavanone D, sophoraisoflavanone A and broussochalcone A in HepG2 cells were 20.9, 37.8, 39.1, 22.1, and 22.0μg/ml, respectively. These results support the use of prenylated flavonoids in Asian traditional medicine to treat microbial infection and indicate a high potential for prenylated flavonoids as antimicrobial agents as well as anti-inflammatory agents.
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.
Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, ...as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. Consistently, purified TUT4/7 selectively recognize and uridylate RNAs with short A-tails (less than ∼25 nt) in vitro. PABPC1 antagonizes uridylation of polyadenylated mRNAs, contributing to the specificity for short A-tails. In cells depleted of TUT4/7, the vast majority of mRNAs lose the oligo-U-tails, and their half-lives are extended. Suppression of mRNA decay factors leads to the accumulation of oligo-uridylated mRNAs. In line with this, microRNA induces uridylation of its targets, and TUT4/7 are required for enhanced decay of microRNA targets. Our study explains the mechanism underlying selective uridylation of deadenylated mRNAs and demonstrates a fundamental role of oligo-U-tail as a molecular mark for global mRNA decay.
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•TUT4 and TUT7 uridylate mRNAs and thereby facilitate mRNA decay•TUT4 and TUT7 selectively uridylate deadenylated mRNAs with a short A-tail (<∼25 nt)•Uridylation is induced by miRNAs and enhances degradation of miRNA targets•Oligo-U-tail serves as a general molecular mark for mRNA decay
Two enzymes, TUT4 and TUT7, selectively recognize and uridylate cellular mRNAs with shortened poly(A) tails to facilitate decay, thus establishing the oligo-U-tail as a general molecular mark for mRNA decay.
LIN28 plays a critical role in developmental transition, glucose metabolism, and tumorigenesis. At the molecular level, LIN28 is known to repress maturation of let-7 microRNAs and enhance translation ...of certain mRNAs. In this study, we obtain a genome-wide view of the molecular function of LIN28A in mouse embryonic stem cells by carrying out RNA crosslinking-immunoprecipitation-sequencing (CLIP-seq) and ribosome footprinting. We find that, in addition to let-7 precursors, LIN28A binds to a large number of spliced mRNAs. LIN28A recognizes AAGNNG, AAGNG, and less frequently UGUG, which are located in the terminal loop of a small hairpin. LIN28A is localized to the periendoplasmic reticulum (ER) area and inhibits translation of mRNAs that are destined for the ER, reducing the synthesis of transmembrane proteins, ER or Golgi lumen proteins, and secretory proteins. Our study suggests a selective regulatory mechanism for ER-associated translation and reveals an unexpected role of LIN28A as a global suppressor of genes in the secretory pathway.
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► CLIP-seq and ribosome footprinting reveal numerous spliced mRNAs as LIN28A targets ► Let-7 is the only effective miRNA target of LIN28A in embryonic stem cells ► LIN28A binds to AAGNNG, AAGNG, and UGUG in the loop of a small hairpin ► LIN28A is localized in peri-ER area and suppresses ER-associated translation
An unexpected role of LIN28A in translational suppression is revealed by a genome-wide search for the functional targets of LIN28A by CLIP-seq and ribosome footprinting.
RNase III Drosha initiates microRNA (miRNA) maturation by cleaving a primary miRNA transcript and releasing a pre-miRNA with a 2 nt 3′ overhang. Dicer recognizes the 2 nt 3′ overhang structure to ...selectively process pre-miRNAs. Here, we find that, unlike prototypic pre-miRNAs (group I), group II pre-miRNAs acquire a shorter (1 nt) 3′ overhang from Drosha processing and therefore require a 3′-end mono-uridylation for Dicer processing. The majority of let-7 and miR-105 belong to group II. We identify TUT7/ZCCHC6, TUT4/ZCCHC11, and TUT2/PAPD4/GLD2 as the terminal uridylyl transferases responsible for pre-miRNA mono-uridylation. The TUTs act specifically on dsRNAs with a 1 nt 3′ overhang, thereby creating a 2 nt 3′ overhang. Depletion of TUTs reduces let-7 levels and disrupts let-7 function. Although the let-7 suppressor, Lin28, induces inhibitory oligo-uridylation in embryonic stem cells, mono-uridylation occurs in somatic cells lacking Lin28 to promote let-7 biogenesis. Our study reveals functional duality of uridylation and introduces TUT7/4/2 as components of the miRNA biogenesis pathway.
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▸ Unlike canonical group I miRNA precursors, group II members have a 1 nt 3′ overhang ▸ Mono-uridylation of group II pre-let-7 promotes Dicer processing ▸ TUT7, TUT4, and TUT2 catalyze pre-let-7 mono-uridylation in cells lacking Lin28 ▸ Lin28 induces oligo-uridylation to inhibit let-7 processing
Group II precursors require mono-uridylation by TUTases to create the overhang of 2 nt required for Dicer processing. In the presence of Lin28, let-7 is preferably oligo-uridylated by TUT4 promoting its degradation, revealing the functional duality of uridylation.
Substantial empirical evidence has indicated impairment in the cognitive functioning of patients with obsessive-compulsive disorder (OCD) despite inconsistencies. Although several confounding factors ...have been investigated to explain the conflicting results, the findings remain mixed. This study aimed to investigate cognitive dysfunction in patients with OCD using a meta-analytic approach.
The PubMed database was searched between 1980 and October 2012, and reference lists of review papers were examined. A total of 221 studies were identified, of which 88 studies met inclusion criteria. Neuropsychological performance and demographic and clinical variables were extracted from each study.
Patients with OCD were significantly impaired in tasks that measured visuospatial memory, executive function, verbal memory and verbal fluency, whereas auditory attention was preserved in these individuals. The largest effect size was found in the ability to recall complex visual stimuli. Overall effect estimates were in the small to medium ranges for executive function, verbal memory and verbal fluency. The effects of potentially confounding factors including educational level, symptom severity, medication status and co-morbid disorders were not significant.
Patients with OCD appear to have wide-ranging cognitive deficits, although their impairment is not so large in general. The different test forms and methods of testing may have influenced the performance of patients with OCD, indicating the need to select carefully the test forms and methods of testing used in future research. The effects of various confounding variables on cognitive functioning need to be investigated further and to be controlled before a definite conclusion can be made.
Background and purpose
Along with intracranial atherosclerotic disease (ICAD), moyamoya disease (MMD) is the most common cause of middle cerebral artery (MCA) occlusion in Asians. Although they have ...differing vascular wall pathologies, conventional angiographic evaluation methods cannot easily differentiate MMD from ICAD in certain situations, such as in young patients with atherosclerotic risk factors. High resolution magnetic resonance imaging (HR‐MRI) findings for the diseased segments of MCAs in MMD and symptomatic ICAD were compared to further elucidate differences in arterial wall changes.
Methods
Angiographically confirmed patients, 12 MMD and 20 ICAD, who suffered a stroke due to MCA occlusion were recruited and underwent HR‐MRI. The size of the outer diameter and other stenotic vessel wall characteristics revealed by HR‐MRI, including enhancement, eccentricity and other lesion patterns, were analyzed by two independent reviewers in a blind fashion.
Results
MMD patients were younger than ICAD patients (32.92 ± 11.08 years vs. 51.85 ± 11.97 years; mean ± SD) and displayed a smaller outer diameter in the stenotic portion (1.61 ± 0.43 mm for MMD vs. 3.03 ± 0.53 mm for ICAD, P < 0.0001). Eccentric lesions (three of 12 in MMD vs. 19 of 20 in ICAD, P < 0.0001) and focal enhancements in diseased areas (two of seven in MMD vs. 13 of 17 in ICAD, P = 0.061) were less common in MMD cases.
Conclusions
Our HR‐MRI findings show that MMD is associated with smaller, concentric occlusive lesions which are rarely enhanced compared with symptomatic ICAD, consistent with the results of previous pathological reports. HR‐MRI may therefore have utility in differentiating MMD from ICAD.
Cervicovaginal microbiota play a critical role in women’s health and reproductive outcomes. Despite being one of the simplest commensal bacterial communities in the human body, we are only beginning ...to appreciate its complex dynamic nature and important role in host immune modulation. In this review, we discuss the “optimal” cervicovaginal bacterial community composition, the impact of microbiota on gynecologic and obstetric outcomes, and the hurdles to developing a deeper mechanistic understanding of the function of the cervicovaginal microbiome. We then describe efforts to durably alter microbial composition in this compartment by promotion of Lactobacillus colonization with probiotics, modulation of vaginal pH, hormonal administration, and the eradication of pathogenic bacteria with antibiotics. Finally, we draw on lessons learned from the deeply investigated gut microbiome to suggest future avenues of research into host-pathogen interactions in the female genital tract.
Why are lactobacilli considered guardians of the female genital tract? Anahtar et al. review the role of cervicovaginal bacteria in gynecologic and obstetric outcomes, describe attempts to shift these communities, and propose a path to understand the mechanisms behind these clinical observations by drawing upon the well-studied gut microbiome.
RNA-binding proteins (RBPs) have essential roles in RNA-mediated gene regulation, and yet annotation of RBPs is limited mainly to those with known RNA-binding domains. To systematically identify the ...RBPs of embryonic stem cells (ESCs), we here employ interactome capture, which combines UV cross-linking of RBP to RNA in living cells, oligo(dT) capture and MS. From mouse ESCs (mESCs), we have defined 555 proteins constituting the mESC mRNA interactome, including 283 proteins not previously annotated as RBPs. Of these, 68 new RBP candidates are highly expressed in ESCs compared to differentiated cells, implicating a role in stem-cell physiology. Two well-known E3 ubiquitin ligases, Trim25 (also called Efp) and Trim71 (also called Lin41), are validated as RBPs, revealing a potential link between RNA biology and protein-modification pathways. Our study confirms and expands the atlas of RBPs, providing a useful resource for the study of the RNA-RBP network in stem cells.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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