Clarithromycin Suppresses Chloride Channel Accessory 1 and Inhibits Interleukin-13-Induced Goblet Cell Hyperplasia in Human Bronchial Epithelial Cells.

Activation of the interleukin-13 (IL-13) receptor leads to signal transducer and activator of transcription 6 (STAT6) activation and subsequent induction of SAM pointed domain containing ETS transcription factor (SPDEF) and chloride channel accessory 1 (CLCA1), increasing secretion of the gel-forming mucin MUC5AC. Activation of the epidermal growth factor receptor (EGFR) also leads to MUC5AC production via extracellular signal-regulated kinase (ERK1/2). We examined the effect of clarithromycin IL-13 signaling leading to production. Normal human bronchial epithelial (NHBE) cells were grown for 14 days at an air-liquid interface (ALI) with IL-13 and/or clarithromycin. Histochemical analysis was performed using hematoxylin and eosin (HE) staining and MUC5AC immunostaining. MUC5AC, SPDEF, and CLCA1 mRNA expression were evaluated by real-time PCR. Western analysis was used to assess phosphorylation of STAT6 and ERK1/2. Clarithromycin decreased IL-13-induced goblet cell hyperplasia and MUC5AC mRNA expression in a dose-dependent manner. Clarithromycin decreased IL-13-stimulated SPDEF and CLCA1 mRNA expression in a dose-dependent manner, and at 32 µg/ml CLCA1 was profoundly decreased (P < 0.001). Although clarithromycin had no effect on STAT6 phosphorylation induced by IL-13, it decreased constitutive phosphorylation of ERK1/2 (P < 0.05).

A dimeric form of N-methoxycarbonyl-2-amino-1,8-naphthyridine bound to the A-A mismatch in the CAG/CAG base triad in dsRNA.

A dimeric form of N-methoxycarbonyl-2-amino-1,8-naphthyridine (MCND) connected at the C2 position with a three-atom linker was examined for the binding to mismatches in double stranded RNA. Despite the fully complementary hydrogen bonding groups to guanine, MCND did not bind to guanine-guanine mismatch but did to adenine-adenine mismatch. The base pairs flanking the mismatch had weak effect on the binding, with showing the strongest binding to the A-A mismatch in the CAG/CAG sequence. The A-A mismatch in the GAC/GAC sequence was a poor substrate for the MCND binding. A monomeric derivative of MCND and another derivative lacking a methylcarbamate group showed negligilble binding to the A-A mismatch and the sequence selectivity. These results are important clues for the better molecular design of RNA binding small molecules.

Perspective: sustainability challenges, opportunities and solutions for long-term ecosystem observations.

As interest in natural capital grows and society increasingly recognizes the value of biodiversity, we must discuss how ecosystem observations to detect changes in biodiversity can be sustained through collaboration across regions and sectors. However, there are many barriers to establishing and sustaining large-scale, fine-resolution ecosystem observations. First, comprehensive monitoring data on both biodiversity and possible anthropogenic factors are lacking. Second, some in situ ecosystem observations cannot be systematically established and maintained across locations. Third, equitable solutions across sectors and countries are needed to build a global network. Here, by examining individual cases and emerging frameworks, mainly from (but not limited to) Japan, we illustrate how ecological science relies on long-term data and how neglecting basic monitoring of our home planet further reduces our chances of overcoming the environmental crisis. We also discuss emerging techniques and opportunities, such as environmental DNA and citizen science as well as using the existing and forgotten sites of monitoring, that can help overcome some of the difficulties in establishing and sustaining ecosystem observations at a large scale with fine resolution. Overall, this paper presents a call to action for joint monitoring of biodiversity and anthropogenic factors, the systematic establishment and maintenance of in situ observations, and equitable solutions across sectors and countries to build a global network, beyond cultures, languages, and economic status. We hope that our proposed framework and the examples from Japan can serve as a starting point for further discussions and collaborations among stakeholders across multiple sectors of society. It is time to take the next step in detecting changes in socio-ecological systems, and if monitoring and observation can be made more equitable and feasible, they will play an even more important role in ensuring global sustainability for future generations. This article is part of the theme issue 'Detecting and attributing the causes of biodiversity change: needs, gaps and solutions'.

Guanine- 5-carboxylcytosine base pairs mimic mismatches during DNA replication.

The genetic information encoded in genomes must be faithfully replicated and transmitted to daughter cells. The recent discovery of consecutive DNA conversions by TET family proteins of 5-methylcytosine into 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine (5caC) suggests these modified cytosines act as DNA lesions, which could threaten genome integrity. Here, we have shown that although 5caC pairs with guanine during DNA replication in vitro, G·5caC pairs stimulated DNA polymerase exonuclease activity and were recognized by the mismatch repair (MMR) proteins. Knockdown of thymine DNA glycosylase increased 5caC in genome, affected cell proliferation via MMR, indicating MMR is a novel reader for 5caC. These results suggest the epigenetic modification products of 5caC behave as DNA lesions.