<p>Arrestins recognize different receptor phosphorylation patterns and convert this information to selective arrestin functions to expand the functional diversity of the G protein-coupled receptor (GPCR) superfamilies. However, the principles governing arrestin-phospho-receptor interactions, as well as the contribution of each single phospho-interaction to selective arrestin structural and functional states, are undefined. Here, we determined the crystal structures of arrestin2 in complex with four different phosphopeptides derived from the vasopressin receptor-2 (V2R) C-tail. A comparison of these four crystal structures with previously solved Arrestin2 structures demonstrated that a single phospho-interaction change results in measurable conformational changes at remote sites in the complex. This conformational bias introduced by specific phosphorylation patterns was further inspected by FRET and 1H NMR spectrum analysis facilitated via genetic code expansion. Moreover, an interdependent phospho-binding mechanism of phospho-receptor-arrestin interactions between different phospho-interaction sites was unexpectedly revealed. Taken together, our results provide evidence showing that phospho-interaction changes at different arrestin sites can elicit changes in affinity and structural states at remote sites, which correlate with selective arrestin functions.In Shark Bay, Western Australia, male bottlenose dolphins form a complex nested alliance hierarchy. At the first level, pairs or trios of unrelated males cooperate to herd individual females. Multiple first-order alliances cooperate in teams (second-order alliances) in the pursuit and defence of females, and multiple teams also work together (third-order alliances). Yet it remains unknown how dolphins classify these nested alliance relationships. We use 30 years of behavioural data combined with 40 contemporary sound playback experiments to 14 allied males, recording responses with drone-mounted video and a hydrophone array. We show that males form a first-person social concept of cooperative team membership at the second-order alliance level, independently of first-order alliance history and current relationship strength across all three alliance levels. Such associative concepts develop through experience and likely played an important role in the cooperative behaviour of early humans. These results provide evidence that cooperation-based concepts are not unique to humans, occurring in other animal societies with extensive cooperation between non-kin.To unravel the pathogenesis of obesity and its complications, we investigate the interplay between circadian clocks and NF-κB pathway in human adipose tissue. The circadian clock function is impaired in omental fat from obese patients. ChIP-seq analyses reveal that the core clock activator, BMAL1 binds to several thousand target genes. NF-κB competes with BMAL1 for transcriptional control of some targets and overall, BMAL1 chromatin binding occurs in close proximity to NF-κB consensus motifs. Obesity relocalizes BMAL1 occupancy genome-wide in human omental fat, thereby altering the transcription of numerous target genes involved in metabolic inflammation and adipose tissue remodeling.  <a href="https://www.selleckchem.com/products/art558.html">ART558 price</a> Eventually, clock dysfunction appears at early stages of obesity in mice and is corrected, together with impaired metabolism, by NF-κB inhibition. Collectively, our results reveal a relationship between NF-κB and the molecular clock in adipose tissue, which may contribute to obesity-related complications.Nanoparticle internalisation is crucial for the precise delivery of drug/genes to its intracellular targets. Conventional quantification strategies can provide the overall profiling of nanoparticle biodistribution, but fail to unambiguously differentiate the intracellularly bioavailable particles from those in tumour intravascular and extracellular microenvironment. Herein, we develop a binary ratiometric nanoreporter (BiRN) that can specifically convert subtle pH variations involved in the endocytic events into digitised signal output, enabling the accurately quantifying of cellular internalisation without introducing extracellular contributions. Using BiRN technology, we find only 10.7-28.2% of accumulated nanoparticles are internalised into intracellular compartments with high heterogeneity within and between different tumour types. We demonstrate the therapeutic responses of nanomedicines are successfully predicted based on intracellular nanoparticle exposure rather than the overall accumulation in tumour mass. This nonlinear optical nanotechnology offers a valuable imaging tool to evaluate the tumour targeting of new nanomedicines and stratify patients for personalised cancer therapy.As an important platform molecule, atropisomeric QUINOL plays a crucial role in the development of chiral ligands and catalysts in asymmetric catalysis. However, efficient approaches towards QUINOL remain scarce, and the resulting high production costs greatly impede the related academic research as well as downstream industrial applications. Here we report a direct oxidative cross-coupling reaction between isoquinolines and 2-naphthols, providing a straightforward and scalable route to acquire the privileged QUINOL scaffolds in a metal-free manner. Moreover, a NHC-catalyzed kinetic resolution of QUINOL N-oxides with high selectivity factor is established to access two types of promising axially chiral Lewis base catalysts in optically pure forms. The utility of this methodology is further illustrated by facile transformations of the products into QUINAP, an iconic ligand in asymmetric catalysis.The mitochondrion is an important sub-cellular organelle responsible for the cellular energetic source and processes. Owing to its unique sensitivity to heat and reactive oxygen species, the mitochondrion is an appropriate target for photothermal and photodynamic treatment for cancer. However, targeted delivery of therapeutics to mitochondria remains a great challenge due to their location in the sub-cellular compartment and complexity of the intracellular environment. Herein, we report a class of the mitochondrion-targeted liposomal delivery platform consisting of a guanidinium-based dendritic peptide moiety mimicking mitochondrion protein transmembrane signaling to exert mitochondrion-targeted delivery with pH sensitive and charge-reversible functions to enhance tumor accumulation and cell penetration. Compared to the current triphenylphosphonium (TPP)-based mitochondrion targeting system, this dendritic lipopeptide (DLP) liposomal delivery platform exhibits about 3.7-fold higher mitochondrion-targeted delivery efficacy.</p>