m 6 A mRNA Methylation in Brown Adipose Tissue Regulates Systemic Insulin Sensitivity via an Inter-Organ Prostaglandin Signaling Axis.

Brown adipose tissue (BAT) has the capacity to regulate systemic metabolism through the secretion of signaling lipids. N6-methyladenosine (m 6 A) is the most prevalent and abundant post-transcriptional mRNA modification and has been reported to regulate BAT adipogenesis and energy expenditure. In this study, we demonstrate that the absence of m 6 A methyltransferase-like 14 (METTL14), modifies the BAT secretome to initiate inter-organ communication to improve systemic insulin sensitivity. Importantly, these phenotypes are independent of UCP1-mediated energy expenditure and thermogenesis. Using lipidomics, we identified prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) as M14 KO -BAT-secreted insulin sensitizers. Notably, circulatory PGE2 and PGF2a levels are inversely correlated with insulin sensitivity in humans. Furthermore, in vivo administration of PGE2 and PGF2a in high-fat diet-induced insulin-resistant obese mice recapitulates the phenotypes of METTL14 deficient animals. PGE2 or PGF2a improves insulin signaling by suppressing the expression of specific AKT phosphatases. Mechanistically, METTL14-mediated m 6 A installation promotes decay of transcripts encoding prostaglandin synthases and their regulators in human and mouse brown adipocytes in a YTHDF2/3-dependent manner. Taken together, these findings reveal a novel biological mechanism through which m 6 A-dependent regulation of BAT secretome regulates systemic insulin sensitivity in mice and humans. Highlights: Mettl14 KO -BAT improves systemic insulin sensitivity via inter-organ communication; PGE2 and PGF2a are BAT-secreted insulin sensitizers and browning inducers;PGE2 and PGF2a sensitize insulin responses through PGE2-EP-pAKT and PGF2a-FP-AKT axis; METTL14-mediated m 6 A installation selectively destabilizes prostaglandin synthases and their regulator transcripts; Targeting METTL14 in BAT has therapeutic potential to enhance systemic insulin sensitivity.

Novel immune subtypes of lung adenocarcinoma identified through bioinformatic analysis.

The magnitude of the immune response is closely associated with clinical outcome in patients with cancer. However, finding potential therapeutic targets for lung cancer in the immune system remains challenging. Here, we constructed a vital immune-prognosis genes (VIPGs) based cluster of lung adenocarcinoma (LUAD) from IMMPORT databases and The Cancer Genome Atlas. A transcription factor regulatory network for the VIPGs was also established. The tumor microenvironment of LUAD was analyzed using the ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) algorithm and single-sample Gene Set Enrichment Analysis. The immune checkpoints and genomic alterations were explored in the different immune clusters. We identified 15 VIPGs for patients with LUAD and clustered the patients into low-immunity and high-immunity subtypes. The immune score, stromal score and ESTIMATE score were significantly higher in the high-immunity subtype, whereas tumor purity was higher in the low-immunity subtype. In addition, the immune checkpoints cytotoxic T lymphocyte associate protein-4(CTLA4), programmed cell death protein-1 and programmed death-ligand were elevated in the low-immunity subtype. The genomic results also showed that the tumor mutation burden was higher in the high-immunity subtype. Finally, Gene Set Enrichment Analysis showed that several immune-related gene sets, including interleukin-2/STAT5 signaling, inflammatory response, interleukin-6/Janus kinase(JAK)/signal transducer and activator of transcription 3 (STAT3) signaling, interferon-gamma response and allograft rejection, were elevated in the high-immunity subtype. Finally, high-immunity patients exhibited greater overall and disease-specific survival outcome compared with low-immunity patients (log rank P = 0.013 and P = 0.0097). Altogether, here we have identified 15 immune-prognosis genes and a potential immune subtype for patients with LUAD, which may provide new insights into the prognosis and treatment of LUAD.

Readily Removable Directing Group Assisted Chemo- and Regioselective C(sp(3))-H Activation by Palladium Catalysis.

Currently used directing groups for selective aliphatic ß-functionalization of carbonyl compounds show excellent reactivity and selectivity with an amide as a linker. Described herein is 2-piconimide, used for the first time with commercially available 2-picolinamide/2-picolic acid as precursors, to direct C-H arylation/alkenylation by palladium catalysis. The directing group is essential for promoting the sequnetial primary and secondary C(sp(3))-H arylation with different aryl iodides in one substrate. The directing group was easily removed under simple reaction conditions at room temperature.

Diversified syntheses of multifunctionalized thiazole derivatives via regioselective and programmed C-H activation.

The sequential construction of diversified multifunctionalized thiazole derivatives through Pd-catalyzed regioselective C-H alkenylation has been accomplished. This versatile approach provides the diversified thiazole derivatives featuring orthogonal substitution patterns at the C-2, C-4 and C-5 positions from mono-substituted (2- or 4-substituted) thiazole derivatives or even more challenging simple thiazole.

Direct cross-coupling of benzyl alcohols to construct diarylmethanes via palladium catalysis.

A direct arylation to furnish diarylmethanes from benzyl alcohols was realized through Pd(PPh3)4-catalyzed Suzuki-Miyaura coupling via benzylic C-O activation in the absence of any additives. The arylation is compatible with various functional groups. This development provides an atom- and step-economic way to approach a diarylmethane scaffold under mild and environmentally benign conditions.

Reigoselective arylation of thiazole derivatives at 5-position via Pd catalysis under ligand-free conditions.

An efficient regioselective arylation of thiazole derivatives via Pd-catalyzed C-H activation is reported. The transformation was hypothesized through a Pd(0/II) catalytic cycle in the absence of special ligand sets. This method provided an efficient process to direct arylation of thiazoles at the 5-position.

Programmed selective sp2 C-O bond activation toward multiarylated benzenes.

A variety of important multiarylated benzenes were efficiently synthesized from phloroglucinol derivatives 1 through sequential cross-couplings via Pd-catalyzed C-OTs, Ni-catalyzed C-OC(O)NEt2, and C-OMe bond activation. High selectivity was achieved based on the rational design and inherent diversity in the reactivity of different C-O bonds.

Palladium-catalyzed trifluoromethylation of aromatic C-H bond directed by an acetamino group.

The first palladium-catalyzed ortho-trifluoromethylation of the aromatic C-H bond directed by an acetamino group is reported. This method provides an efficient and green approach to synthesize the highly biological potential key structure of ortho-CF(3) acetanilides and anilines.