KIN‐4/MAST kinase promotes PTEN‐mediated longevity of Caenorhabditis elegans via binding through a PDZ domain

PDZ domain‐containing proteins (PDZ proteins) act as scaffolds for protein–protein interactions and are crucial for a variety of signal transduction processes. However, the role of PDZ proteins in organismal lifespan and aging remains poorly understood. Here, we demonstrate that KIN‐4, a PDZ domain‐containing microtubule‐associated serine‐threonine (MAST) protein kinase, is a key longevity factor acting through binding PTEN phosphatase in Caenorhabditis elegans. Through a targeted genetic screen for PDZ proteins, we find that kin‐4 is required for the long lifespan of daf‐2/insulin/IGF‐1 receptor mutants. We then show that neurons are crucial tissues for the longevity‐promoting role of kin‐4. We find that the PDZ domain of KIN‐4 binds PTEN, a key factor for the longevity of daf‐2 mutants. Moreover, the interaction between KIN‐4 and PTEN is essential for the extended lifespan of daf‐2 mutants. As many aspects of lifespan regulation in C. elegans are evolutionarily conserved, MAST family kinases may regulate aging and/or age‐related diseases in mammals through their interaction with PTEN.     

Time-Restricted Feeding Prevents Obesity and Metabolic Syndrome in Mice Lacking a Circadian Clock

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Family Ismaridae Thomson (Hymenoptera,Diaprioidea), new to fauna of Iran

Occurrence of the family Ismaridae Thomson is recorded for the first time from Iran, represented by a single species, Ismarus rugulosus Förster, 1850. A series of diagnostic characters and morphometric ratios for this species is presented, as well as a distribution map throughout the Holarctic region.     

Effect of temperature on reproduction and parasitism of the egg parasitoid,Anastatus orientalis (Hymenoptera: Eupelmidae)

Anastatus orientalis is a solitary endoparasitoid of Lycorma delicatula (Hemiptera: Fulgoridae) eggs. We investigated the development, longevity, fecundity, and sex ratio of A. orientalis on different temperatures to establish the optimal temperature condition for laboratory mass rearing. There were significant differences in its development and longevity between 15 °C and the rest of temperature conditions (20, 25, and 30 °C), among which were no significant differences. The average number of eggs laid by A. orientalis was higher at 20 and 25 °C, but there was no statistically significant difference in its fecundity between the two temperatures. More females emerged at 15 and 20 °C than higher temperatures.Parasitisms of A. orientalis varied with host egg ages and densities. Even in 14 day old eggs of L. delicatula, parasitoids successfully emerged from 92.3% of the parasitized eggs. On the other hand, parasitism was lowest (13.8%) on just before hatching eggs. Parasitism was negatively dependent on host density.Oviposition behavior for A. orientalis primarily occurred at 1400–1600 h, not at 2400–0800 h. The majority of this parasitoid's emergence occurred at 0800–1000 h, largely before noon. These results may be useful for controlling the adequate time for supplying host eggs and release density of this parasitoid as well as for potentially predicting the accurate time for securing parasitoid adults in laboratory mass rearing of A. orientalis.     

Real microgravity condition promoted regeneration capacity of induced pluripotent stem cells during the TZ‐1 space mission

Induced pluripotent stem cells (iPSCs) are reprogrammed somatic cells that gained self‐renewal and differentiation capacity similar to embryonic stem cells. Taking the precious opportunity of the TianZhou‐1 spacecraft mission, we studied the effect of space microgravity (µg) on the self‐renewal capacity of iPSCs. Murine iPSCs carrying pluripotency reporter Oct4‐GFP were used. The Oct4‐EGFP‐iPSCs clones were loaded into the bioreactor and exposed to μg in outer space for 14 days. The control experiment was performed in identical device but on the ground in earth gravity (1 g). iPSCs clones were compact and highly expressed Oct4 before launch. In μg condition, cells in iPSC clones spread out more rapidly than those in ground 1 g condition during the first 3 days after launch. However, in 1 g condition, as the cell density increases, the Oct4‐GFP signal dropped significantly during the following 3 days. Interestingly, in μg condition, iPSCs originated from the spread‐out clones during the first 3 days appeared to cluster together and reform colonies that activated strong Oct4 expression. On the other hand, iPSC clones in 1 g condition were not able to recover Oct4 expression after overgrown. Our study for the first time performed real‐time imaging on the proliferation process of iPSCs in space and found that in μg condition, cell behaviour appeared to be more dynamic than on the ground.     

Unexpected equivalent potency of a constrained chromene enantiomeric pair rationalized by co-crystal structures in complex with estrogen receptor alpha

Despite tremendous progress made in the understanding of the ERα signaling pathway and the approval of many therapeutic agents, ER+?breast cancer continues to be a leading cause of cancer death in women. We set out to discover compounds with a dual mechanism of action in which they not only compete with estradiol for binding with ERα, but also can induce the degradation of the ERα protein itself. We were attracted to the constrained chromenes containing a tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective estrogen receptor modulators (SERMs). Incorporation of a fluoromethyl azetidine side chain yielded highly potent and efficacious selective estrogen receptor degraders (SERDs), such as 16aa and surprisingly, also its enantiomeric pair 16ab. Co-crystal structures of the enantiomeric pair 16aa and 16ab in complex with ERα revealed default (mimics the A-D rings of endogenous ligand estradiol) and core-flipped binding modes, rationalizing the equivalent potency observed for these enantiomers in the ERα degradation and MCF-7 anti-proliferation assays.     

SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel,CNS penetrant tricyclic M4 PAMs

This letter describes progress towards an M₄ PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M₄ PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.     

The maize α-zein promoter can be utilized as a strong inducer of cellulase enzyme expression in maize kernels

Transgenic Research - Expression of recombinant proteins in plants is a technology for producing vaccines, pharmaceuticals and industrial enzymes. For the past several years, we have produced...