N 6 -methyladenosine (m 6 A) is the most abundant internal modification in RNAs and plays regulatory roles in a variety of biological and physiological processes. Despite its important roles, the molecular mechanism underlying m 6 A-mediated gene regulation is poorly understood. Here, we show that m 6 A-containing RNAs are subject to endoribonucleolytic cleavage via YTHDF2 (m 6 A reader protein), HRSP12 (adaptor protein), and RNase P/MRP (endoribonucleases). We demonstrate that HRSP12 functions as an adaptor to bridge YTHDF2 and RNase P/MRP, eliciting rapid degradation of YTHDF2-bound RNAs. Transcriptome-wide analyses show that m 6 A RNAs that are preferentially targeted for endoribonucleolytic cleavage have an HRSP12-binding site and a RNase P/MRP-directed cleavage site upstream and downstream of the YTHDF2-binding site, respectively. We also find that a subset of m 6 A-containing circular RNAs associates with YTHDF2 in an HRSP12-dependent manner and is selectively downregulated by RNase P/MRP. Thus, our data expand the known functions of RNase P/MRP to endoribonucleolytic cleavage of m 6 A RNAs.

N 6 -Methyladenosine (m 6 A), the most prevalent internal modification associated with eukaryotic mRNAs, influences many steps of mRNA metabolism, including splicing, export, and translation, as well as stability. Recent studies have revealed that m 6 A-containing mRNAs undergo one of two distinct pathways of rapid degradation: deadenylation via the YT521-B homology (YTH) domain-containing family protein 2 (YTHDF2; an m 6 A reader protein)-CCR4/NOT (deadenylase) complex or endoribonucleolytic cleavage by the YTHDF2-HRSP12-ribonuclease (RNase) P/mitochondrial RNA-processing (MRP) (endoribonuclease) complex. Some m 6 A-containing circular RNAs (circRNAs) are also subject to endoribonucleolytic cleavage by YTHDF2-HRSP12-RNase P/MRP. Here, we highlight recent progress on the molecular mechanisms underlying rapid mRNA degradation via m 6 A and describe our current understanding of the dynamic regulation of m 6 A-mediated mRNA decay through the crosstalk between m 6 A (or YTHDF2) and other cellular factors. RNA Modification: An Emerging Layer of Post-Transcriptional Gene RegulationMany recent studies point to the role of RNA modification as a mode of post-transcriptional gene regulation and this field has been termed 'epitranscriptomics' [1-4]. To date, approximately 150 post-transcriptional modifications have been associated with various RNA species, including mRNAs, tRNAs, rRNAs, noncoding RNAs (ncRNAs), and viral RNA genomes [5][6][7]. In this review, we summarize recent reports on m 6 A deposition and function. In particular, we discuss recent findings regarding how m 6 A contributes to mRNA stability at the molecular level. HighlightsN 6 -Methyladenosine (m 6 A) as an mRNA modification plays multiple roles in various steps/characteristics of mRNA processing and metabolism, such as splicing, export, translation, and stability.YTHDF2 preferentially recognizes m 6 A and recruits RNA-degrading enzymes or adaptor proteins to trigger rapid degradation of the m 6 A-containing mRNA.Depending on the presence of HRSP12binding sites in m 6 A-containing mRNAs, YTHDF2 elicits one of two RNA decay pathways: deadenylation by the YTHDF2-CCR4/NOT deadenylase complex or endoribonucleolytic cleavage via the YTHDF2-HRSP12-RNase P/MRP complex.The stability of m 6 A-containing mRNAs is regulated by the dynamic crosstalk between m 6 A and other cellular factors, such as RNA-binding proteins, RNA structures, and/or other types of modification.

An extremely high degree of circularly polarized photoluminescence (CPPL) and electroluminescence (CPEL) (dissymmetry factor values: |g | = 0.72 and |g | = 1.13) are generated from twisted stacking of achiral conjugated polymer induced by nonemitting chiral dopant of high helical twisting power for the first time. Using a theoretical analysis incorporating the Stokes parameter, the twisting angle and birefringence of the aligned conjugated polymer, and the degree of linear polarization in the emitted light are found to make a roughly equal contribution to the degree of CPEL as to the degree of CPPL. Moreover, it is also found that the location of the recombination zone within the emitting layer is a crucial parameter for determining the difference in the dissymmetry factor between CPEL and CPPL. This result is applied to an organic light-emitting display to improve the luminous efficiency by 60%.

The rigidity and relatively primitive modes of operation of catheters equipped with sensing or actuation elements impede their conformal contact with soft-tissue surfaces, limit the scope of their uses, lengthen surgical times and increase the need for advanced surgical skills. Here, we report materials, device designs and fabrication approaches for integrating advanced electronic functionality with catheters for minimally invasive forms of cardiac surgery. By using multiphysics modelling, plastic heart models and Langendorff animal and human hearts, we show that soft electronic arrays in multilayer configurations on endocardial balloon catheters can establish conformal contact with curved tissue surfaces, support high-density spatiotemporal mapping of temperature, pressure and electrophysiological parameters and allow for programmable electrical stimulation, radiofrequency ablation and irreversible electroporation. Integrating multimodal and multiplexing capabilities into minimally invasive surgical instruments may improve surgical performance and patient outcomes.Minimally invasive surgeries involve the insertion of advanced diagnostic and therapeutic tools through small percutaneous incisions for treatment of cardiovascular diseases, cancers and other health conditions, with fast recovery times and low risks compared with those of conventional procedures 1,2 . Catheters represent one of the most compelling devices for such purposes due to their capabilities in deploying medical devices (for example, intravascular stents or heart-valve prostheses), capturing information during surgical procedures (for example, force, temperature or electrograms) and/or delivering forces, electromagnetic energy, thermal stimuli and/or biomaterials (for example, drugs, cells or nanoparticles) to targeted sites on or within soft tissues 3,4 . Although these catheter-based approaches have widespread uses in modern medicine, they suffer from (1) mechanical rigidity or insufficient compliance, leading to non-ideal interfaces with soft tissues and low coupling efficiency 5 , Han et al.

Wide-spread protozoan parasites carry endosymbiotic dsRNA viruses with uncharted implications to the human host. Among them, Trichomonas vaginalis, a parasite adapted to the human genitourinary tract, infects globally ∼250 million each year rendering them more susceptible to devastating pregnancy complications (especially preterm birth), HIV infection and HPV-related cancer. While first-line antibiotic treatment (metronidazole) commonly kills the protozoan pathogen, it fails to improve reproductive outcome. We show that endosymbiotic Trichomonasvirus, highly prevalent in T. vaginalis clinical isolates, is sensed by the human epithelial cells via Toll-like receptor 3, triggering Interferon Regulating Factor -3, interferon type I and proinflammatory cascades previously implicated in preterm birth and HIV-1 susceptibility. Metronidazole treatment amplified these proinflammatory responses. Thus, a new paradigm targeting the protozoan viruses along with the protozoan host may prevent trichomoniasis-attributable inflammatory sequelae.

Mitochondria play key roles in cellular immunity. How mitochondria contribute to organismal immunity remains poorly understood. Here, we show that HSP-60/HSPD1, a major mitochondrial chaperone, boosts anti-bacterial immunity through the up-regulation of p38 MAP kinase signaling. We first identify 16 evolutionarily conserved mitochondrial components that affect the immunity of against pathogenic (PA14). Among them, the mitochondrial chaperone HSP-60 is necessary and sufficient to increase resistance to PA14. We show that HSP-60 in the intestine and neurons is crucial for the resistance to PA14. We then find that p38 MAP kinase signaling, an evolutionarily conserved anti-bacterial immune pathway, is down-regulated by genetic inhibition of , and up-regulated by increased expression of Overexpression of , the mammalian ortholog of, increases p38 MAP kinase activity in human cells, suggesting an evolutionarily conserved mechanism. Further, cytosol-localized HSP-60 physically binds and stabilizes SEK-1/MAP kinase kinase 3, which in turn up-regulates p38 MAP kinase and increases immunity. Our study suggests that mitochondrial chaperones protect host eukaryotes from pathogenic bacteria by up-regulating cytosolic p38 MAPK signaling.

Apigenin (4',5,7-trihydroxyflavone) is a natural flavonoid, shown to have chemopreventive and/or anticancer properties in a variety of human cancer cells. The involvement of autophagy in apigenin-induced apoptotic cell death of HCT116 human colon cancer cells was investigated. Apigenin induced suppression of cell growth in a concentration-dependent manner in HCT116 cells. Flow cytometric analyses indicated that apigenin resulted in G2/M phase arrest. This flavone also suppressed the expression of both cyclin B1 and its activating partners, Cdc2 and Cdc25c, whereas the expression of cell cycle inhibitors, such as p53 and p53-dependent p21(CIP1/WAF1), was increased after apigenin treatment. Apigenin induced poly (ADP-ribose) polymerase (PARP) cleavage and decreased the levels of procaspase-8, -9 and -3. In addition, the apigenin-treated cells exhibited autophagy, as characterized by the appearance of autophagosomes under fluorescence microscopy and the accumulation of acidic vesicular organelles by flow cytometry. Furthermore, the results of the western blot analysis revealed that the levels of LC3-II, the processed form of LC3-I, was increased by apigenin. Treatment with the autophagy inhibitor 3-methyladenine (3-MA) significantly enhanced the apoptosis induced by apigenin, which was accompanied by an increase in the levels of PARP cleavage. These results indicate that apigenin has apoptosis- and autophagy-inducing effects in HCT116 colon cancer cells. Autophagy plays a cytoprotective role in apigenin-induced apoptosis, and the combination of apigenin and an autophagy inhibitor may be a promising strategy for colon cancer control.

BackgroundThe Supplemental Nutrition Assistance Program (SNAP) provides approximately US$70 billion annually to support food purchases by low-income households, supporting approximately 1 in 7 Americans. In the 2018 Farm Bill, potential SNAP revisions to improve diets and health could include financial incentives, disincentives, or restrictions for certain foods. However, the overall and comparative impacts on health outcomes and costs are not established. We aimed to estimate the health impact, program and healthcare costs, and cost-effectiveness of food incentives, disincentives, or restrictions in SNAP.Methods and findingsWe used a validated microsimulation model (CVD-PREDICT), populated with national data on adult SNAP participants from the National Health and Nutrition Examination Survey (NHANES) 2009–2014, policy effects from SNAP pilots and food pricing meta-analyses, diet–disease effects from meta-analyses, and policy, food, and healthcare costs from published literature to estimate the overall and comparative impacts of 3 dietary policy interventions: (1) a 30% incentive for fruits and vegetables (F&V), (2) a 30% F&V incentive with a restriction of sugar-sweetened beverages (SSBs), and (3) a broader incentive/disincentive program for multiple foods that also preserves choice (SNAP-plus), combining 30% incentives for F&V, nuts, whole grains, fish, and plant-based oils and 30% disincentives for SSBs, junk food, and processed meats. Among approximately 14.5 million adults on SNAP at baseline with mean age 52 years, our simulation estimates that the F&V incentive over 5 years would prevent 38,782 cardiovascular disease (CVD) events, gain 18,928 quality-adjusted life years (QALYs), and save $1.21 billion in healthcare costs. Adding SSB restriction increased gains to 93,933 CVD events prevented, 45,864 QALYs gained, and $4.33 billion saved. For SNAP-plus, corresponding gains were 116,875 CVD events prevented, 56,056 QALYs gained, and $5.28 billion saved. Over a lifetime, the F&V incentive would prevent approximately 303,900 CVD events, gain 649,000 QALYs, and save $6.77 billion in healthcare costs. Adding SSB restriction increased gains to approximately 797,900 CVD events prevented, 2.11 million QALYs gained, and $39.16 billion in healthcare costs saved. For SNAP-plus, corresponding gains were approximately 940,000 CVD events prevented, 2.47 million QALYs gained, and $41.93 billion saved. From a societal perspective (including programmatic costs but excluding food subsidy costs as an intra-societal transfer), all 3 scenarios were cost-saving. From a government affordability perspective (i.e., incorporating food subsidy costs, including for children and young adults for whom no health gains were modeled), the F&V incentive was of low cost-effectiveness at 5 years (incremental cost-effectiveness ratio: $548,053/QALY) but achieved cost-effectiveness ($66,525/QALY) over a lifetime. Adding SSB restriction, the intervention was cost-effective at 10 years ($68,857/QALY) and very cost-effective at 20 years ($26,435/QA...