Circadian clocks generate endogenous rhythms in most organisms from cyanobacteria to humans and facilitate entrainment to environmental diurnal cycles, thus conferring a fitness advantage. Both transcriptional and posttranslational mechanisms are prominent in the basic network architecture of circadian systems. Posttranscriptional regulation, including mRNA processing, is emerging as a critical step for clock function. However, little is known about the molecular mechanisms linking RNA metabolism to the circadian clock network. Here, we report that a conserved SNW/Ski-interacting protein (SKIP) domain protein, SKIP, a splicing factor and component of the spliceosome, is involved in posttranscriptional regulation of circadian clock genes in Arabidopsis thaliana. Mutation in SKIP lengthens the circadian period in a temperature-sensitive manner and affects light input and the sensitivity of the clock to light resetting. SKIP physically interacts with the spliceosomal splicing factor Ser/Arg-rich protein45 and associates with the pre-mRNA of clock genes, such as PSEUDORESPONSE REGULATOR7 (PRR7) and PRR9, and is necessary for the regulation of their alternative splicing and mRNA maturation. Genome-wide investigations reveal that SKIP functions in regulating alternative splicing of many genes, presumably through modulating recognition or cleavage of 59 and 39 splice donor and acceptor sites. Our study addresses a fundamental question on how the mRNA splicing machinery contributes to circadian clock function at a posttranscriptional level.

We present a structural engineered air-stable conducting polymer with high electrical conductivity and carrier mobility.

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Well-adhered, conformal, thin (<100 nm) coatings can easily be obtained by chemical vapor deposition (CVD) for a variety of technological applications. Room temperature modification with functional polymers can be achieved on virtually any substrate: organic, inorganic, rigid, flexible, planar, three-dimensional, dense, or porous. In CVD polymerization, the monomer(s) are delivered to the surface through the vapor phase and then undergo simultaneous polymerization and thin film formation. By eliminating the need to dissolve macromolecules, CVD enables insoluble polymers to be coated and prevents solvent damage to the substrate. CVD film growth proceeds from the substrate up, allowing for interfacial engineering, real-time monitoring, and thickness control. Initiated-CVD shows successful results in terms of rationally designed micro- and nanoengineered materials to control molecular interactions at material surfaces. The success of oxidative-CVD is mainly demonstrated for the deposition of organic conducting and semiconducting polymers.

Molecular engineering of intra- and interchain interactions transforms polymers into good heat conductors.

SUMMARY Since persister cells cause chronic infections and since Escherichia coli toxin MqsR increases persisters, we used protein engineering to increase the toxicity of MqsR to gain insights into persister cell formation. Through two amino acid replacements that increased the stability of MqsR, toxicity and persistence were increased. A whole transcriptome study revealed that the MqsR variant increased persistence by repressing genes for acid resistance, multidrug resistance, and osmotic resistance. Corroborating these microarray results, deletion of rpoS as well as the genes that the master stress response regulator RpoS controls increased persister formation dramatically to the extent that nearly the whole population became persistent. Furthermore, wild-type cells stressed by prior treatment to acid or hydrogen peroxide increased persistence 12,000-fold. Whole-transcriptome analyses of persister cells generated by two different methods (wild-type cells pretreated with hydrogen peroxide and the rpoS deletion) corroborated the importance of suppressing RpoS in persister cell formation. Therefore, the more toxic MqsR increases persistence by decreasing the ability of the cell to respond to antibiotic stress through its RpoS-based regulation of acid resistance, multidrug resistance, and osmotic resistance systems.

BackgroundAccumulating evidence has revealed the critical roles of N6-methyladenosine (m6A) modification of mRNA in various cancers. However, the biological function and regulation of m6A in bladder cancer (BC) are not yet fully understood.MethodsWe performed cell phenotype analysis and established in vivo mouse xenograft models to assess the effects of m6A-modified ITGA6 on BC growth and progression. Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation and luciferase reporter and mutagenesis assays were used to define the mechanism of m6A-modified ITGA6. Immunohistochemical analysis was performed to assess the correlation between METTL3 and ITGA6 expression in bladder cancer patients.FindingsWe show that the m6A writer METTL3 and eraser ALKBH5 altered cell adhesion by regulating ITGA6 expression in bladder cancer cells. Moreover, upregulation of ITGA6 is correlated with the increase in METTL3 expression in human BC tissues, and higher expression of ITGA6 in patients indicates a lower survival rate. Mechanistically, m6A is highly enriched within the ITGA6 transcripts, and increased m6A methylations of the ITGA6 mRNA 3’UTR promotes the translation of ITGA6 mRNA via binding of the m6A readers YTHDF1 and YTHDF3. Inhibition of ITGA6 results in decreased growth and progression of bladder cancer cells in vitro and in vivo. Furthermore, overexpression of ITGA6 in METTL3-depleted cells partially restores the BC adhesion, migration and invasion phenotypes.InterpretationOur results demonstrate an oncogenic role of m6A-modified ITGA6 and show its regulatory mechanisms in BC development and progression, thus identifying a potential therapeutic target for BC.FundThis work was supported by National Natural Science Foundation of China (81772699, 81472999).