Holocene abrupt cooling events have long attracted attention in academia due to public concern that similar rapid changes may reappear in the near future. Thus, considerable progress has been made toward understanding these short-term cooling events in the Northern Hemisphere, particularly in Europe and North America. However, few relevant studies have been conducted in coastal East Asia due to a lack of undisturbed sample materials appropriate for paleoclimate studies. In this study, we examined Holocene abrupt drying events and the Holocene climate optimum (HCO) based on a new high-resolution multi-proxy record (pollen, mean grain size, total organic carbon, carbon/nitrogen ratio) from the south coast of Korea. Possible cultural impacts of the events were also explored using summed probability distributions (SPDs) of archaeological radiocarbon dates. Our arboreal pollen percentage (AP) data clearly indicated drying events centered at 9.8 ka, 9.2 ka, 8.2 ka, 4.7 ka, 4.2 ka, 3.7 ka, 3.2 ka, 2.8 ka, and 2.4 ka BP. The AP data also indicated that forests were severely damaged by a two-step successive drying event during the period from 8.4 ka to 8 ka BP and that the HCO lasted from ca. 7.6 ka to ca. 4.8 ka BP. According to the results of a correlation analysis, climate variations on the Korean peninsula were possibly controlled by shifts in western tropical Pacific (WTP) sea surface temperatures during the past ~5500 years. Simultaneous declines in the SPDs and AP from 2.8 ka to 2.3 ka BP may reflect a demographic reduction attributable to rapid climate deterioration on the peninsula. Refugee agriculturalists might have immigrated to Japan and developed the Yayoi culture. In this study, the 2.8 ka event and its societal impact are recognized clearly for the first time in coastal East Asia.
A macrocyclic peptide scaffold with well-established structure−property relationship is desirable for tackling undruggable targets. Here, we adopted a natural macrocycle, cyclosporin O (CsO) and its derivatives (CP1−3), and evaluated the impact of conformation on membrane permeability, cyclophilin A (CypA) binding, and the pharmacokinetic (PK) profile. In nonpolar media, CsO showed a similar conformation to cyclosporin A (CsA), a well-known chameleonic macrocycle, but less chameleonic behavior in a polar environment. The weak chameleonicity of CsO resulted in decreased membrane permeability; however, the more rigid conformation of CsO was not detrimental to its PK profile. CsO exhibited a higher plasma concentration than CsA, which resulted from minimal CypA binding and lower accumulation in red blood cells and moderate oral bioavailability (F = 12%). Our study aids understanding of CsO, a macrocyclic peptide that is less explored than CsA but with greater potential for diversity generation and rational design.
Background
Although microbioa‐based therapies have shown putative effects on the treatment of non‐alcoholic fatty liver disease (NAFLD), it is not clear how microbiota‐derived metabolites contribute to the prevention of NAFLD. We explored the metabolomic signature of
Lactobacillus lactis
and
Pediococcus pentosaceus
in NAFLD mice and its association in NAFLD patients.
Methods
We used Western diet‐induced NAFLD mice, and
L. lactis
and
P. pentosaceus
were administered to animals in the drinking water at a concentration of 10
9
CFU/g for 8 weeks. NAFLD severity was determined based on liver/body weight, pathology and biochemistry markers. Caecal samples were collected for the metagenomics by 16S rRNA sequencing. Metabolite profiles were obtained from caecum, liver and serum. Human stool samples (healthy control [
n
= 22] and NAFLD patients [
n
= 23]) were collected to investigate clinical reproducibility for microbiota‐derived metabolites signature and metabolomics biomarker.
Results
L. lactis
and
P. pentosaceus
supplementation effectively normalized weight ratio, NAFLD activity score, biochemical markers, cytokines and gut‐tight junction. While faecal microbiota varied according to the different treatments, key metabolic features including short chain fatty acids (SCFAs), bile acids (BAs) and tryptophan metabolites were analogously restored by both probiotic supplementations. The protective effects of indole compounds were validated with in vitro and in vivo models, including anti‐inflammatory effects. The metabolomic signatures were replicated in NAFLD patients, accompanied by the comparable levels of
Firmicutes
/
Bacteroidetes
ratio, which was significantly higher (4.3) compared with control (0.6). Besides, the consequent biomarker panel with six stool metabolites (indole, BAs, and SCFAs) showed 0.922 (area under the curve) in the diagnosis of NAFLD.
Conclusions
NAFLD progression was robustly associated with metabolic dys‐regulations in the SCFAs, bile acid and indole compounds, and NAFLD can be accurately diagnosed using the metabolites.
L. lactis
and
P. pentosaceus
ameliorate NAFLD progression by modulating gut metagenomic and metabolic environment, particularly tryptophan pathway, of the gut‐liver axis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.