Antiaging diets: Separating fact from fiction Lee, Mitchell B; Hill, Cristal M; Bitto, Alessandro ...
Science (American Association for the Advancement of Science),
2021-Nov-19, Letnik:
374, Številka:
6570
Journal Article
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Caloric restriction has been known for nearly a century to extend life span and delay age-associated pathology in laboratory animals. More recently, alternative “antiaging” diet modalities have been ...described that provide new mechanistic insights and potential clinical applications. These include intermittent fasting, fasting-mimicking diets, ketogenic diets, time-restricted feeding, protein restriction, and dietary restriction of specific amino acids. Despite mainstream popularization of some of these diets, many questions remain about their efficacy outside of a laboratory setting. Studies of these interventions support at least partially overlapping mechanisms of action and provide insights into what appear to be highly conserved mechanisms of biological aging.
We have developed a photoinduced copper‐catalyzed alkylation of terminal alkynes with primary, secondary, or tertiary alkyl iodides as electrophiles. The reaction has a broad substrate scope and can ...be successfully performed in the presence of ester, nitrile, aryl halide, ketone, sulfonamide, epoxide, alcohol, and amide functional groups. The alkylation is promoted by blue light (λ≈450 nm) and proceeds at room temperature in the absence of any additional metal catalysts. The use of a terpyridine ligand is essential for the success of the reaction and is shown to prevent photoinduced copper‐catalyzed polymerization of the starting materials.
Under blue light: The photoinduced copper‐catalyzed alkylation of terminal alkynes with primary, secondary, or tertiary alkyl iodides is promoted by blue light (λ≈450 nm) and proceeds at room temperature in the absence of any additional metal catalysts. The use of a terpyridine ligand is essential for the success of the reaction as it prevents photoinduced copper‐catalyzed polymerization of the starting materials.
This paper describes a detailed mechanistic study of the silver-catalyzed Z-selective hydroalkylation of terminal alkynes. Considering the established mechanistic paradigms for
-selective ...hydroalkylation of alkynes, we explored a mechanism based on the radical carbometalation of alkynes. Experimental results have provided strong evidence against the initially proposed radical mechanism and have led us to propose a new mechanism for the
-selective hydroalkylation of alkynes based on boronate formation and a 1,2-metalate shift. The new mechanism provides a rationale for the excellent Z-selectivity observed in the reaction. A series of stoichiometric experiments has probed the feasibility of the proposed elementary steps and revealed an additional role of the silver catalyst in the protodeboration of an intermediate. Finally, a series of kinetic measurements, KIE experiments, and competition experiments allowed us to identify the turnover limiting step and the resting state of the catalyst. We believe that the results of this study will be useful in the further exploration and development of related transformations of alkynes.
This work characterizes a commercially available europium-doped strontium iodide detector recently developed by Radiation Monitoring Devices (RMD). The detector has been chosen for a space-based ...mission scheduled to launch in early 2017. The primary goal of this work was to characterize the detector׳s response over the expected operational range of −10°C to 30°C as well as the expected operational voltage range of +26.5–+28.5V and identify background interferences that may develop due to neutron activation produced by cosmic-ray interactions. The 8mm×8mm×20mm detectors use KETEK silicon photomultipliers (SiPM), with an active area of 6mmx6mm (KETEK PM6660). Our results show substantial integral nonlinearity due to the SiPM ranging from 0% to 25% at room temperature over the energy range of 80–2614keV. The nonlinearity, a function of temperature and overvoltage, leads to an underestimate of the full width at half max (FWHM), which is 2.6% uncorrected at 662keV and 3.8% corrected at 662keV. The temperature dependence of the detector results in a noise threshold that increases substantially above 30°C due to the SiPM dark rate. In an effort to simulate the harsh environment of space, neutron activation of the detector was also explored. Gamma-ray lines at 127keV and 164keV were observed in the detector along with Kα x-rays associated with europium. Beta decay from europium- and iodine-activation products were also observed within the detector.
Targeting aging is the future of twenty-first century preventative medicine. Small molecule interventions that promote healthy longevity are known, but few are well-developed and discovery of novel, ...robust interventions has stagnated. To accelerate longevity intervention discovery and development, high-throughput systems are needed that can perform unbiased drug screening and directly measure lifespan and healthspan metrics in whole animals.
C. elegans
is a powerful model system for this type of drug discovery. Combined with automated data capture and analysis technologies, truly high-throughput longevity drug discovery is possible. In this perspective, we propose the “million-molecule challenge”, an effort to quantitatively assess 1,000,000 interventions for longevity within five years. The WormBot-AI, our best-in-class robotics and AI data analysis platform, provides a tool to achieve the million-molecule challenge for pennies per animal tested.
During infection, the bacterial pathogen Legionella pneumophila manipulates a variety of host cell signaling pathways, including the Hippo pathway which controls cell proliferation and ...differentiation in eukaryotes. Our previous studies revealed that L. pneumophila encodes the effector kinase LegK7 which phosphorylates MOB1A, a highly conserved scaffold protein of the Hippo pathway. Here, we show that MOB1A, in addition to being a substrate of LegK7, also functions as an allosteric activator of its kinase activity. A crystallographic analysis of the LegK7–MOB1A complex revealed that the N-terminal half of LegK7 is structurally similar to eukaryotic protein kinases, and that MOB1A directly binds to the LegK7 kinase domain. Substitution of interface residues critical for complex formation abrogated allosteric activation of LegK7 both in vitro and within cells and diminished MOB1A phosphorylation. Importantly, the N-terminal extension (NTE) of MOB1A not only regulated complex formation with LegK7 but also served as a docking site for downstream substrates such as the transcriptional coregulator YAP1. Deletion of the NTE from MOB1A or addition of NTE peptides as binding competitors attenuated YAP1 recruitment to and phosphorylation by LegK7. By providing mechanistic insight into the formation and regulation of the LegK7–MOB1A complex, our study unravels a sophisticated molecular mimicry strategy that is used by L. pneumophila to take control of the host cell Hippo pathway.
The yeast genome becomes unstable during stress, which often results in adaptive aneuploidy, allowing rapid activation of protective mechanisms that restore cellular homeostasis. In this study, we ...performed a genetic screen in Saccharomyces cerevisiae to identify genome adaptations that confer resistance to tunicamycin-induced endoplasmic reticulum (ER) stress. Whole-genome sequencing of tunicamycin-resistant mutants revealed that ER stress resistance correlated significantly with gains of chromosomes II and XIII. We found that chromosome duplications allow adaptation of yeast cells to ER stress independently of the unfolded protein response, and that the gain of an extra copy of chromosome II alone is sufficient to induce protection from tunicamycin. Moreover, the protective effect of disomic chromosomes can be recapitulated by overexpression of several genes located on chromosome II. Among these genes, overexpression of UDP-N-acetylglucosamine-1-P transferase (ALG7), a subunit of the 20S proteasome (PRE7), and YBR085C-A induced tunicamycin resistance in wild-type cells, whereas deletion of all three genes completely reversed the tunicamycin-resistance phenotype. Together, our data demonstrate that aneuploidy plays a critical role in adaptation to ER stress by increasing the copy number of ER stress protective genes. While aneuploidy itself leads to proteotoxic stress, the gene-specific effects of chromosome II aneuploidy counteract the negative effect resulting in improved protein folding.
Noble metal nanoparticles have been sought after in cancer nanomedicine during the past two decades, owing to the unique localized surface plasmon resonance that induces strong absorption and ...scattering properties of the nanoparticles. A popular application of noble metal nanoparticles is photothermal therapy, which destroys cancer cells by heat generated by laser irradiation of the nanoparticles. Gold nanorods have stood out as one of the major types of noble metal nanoparticles for photothermal therapy due to the facile tuning of their optical properties in the tissue penetrative near infrared region, strong photothermal conversion efficiency, and long blood circulation half-life after surface modification with stealthy polymers. In this review, we will summarize the optical properties of gold nanorods and their applications in photothermal therapy. We will also discuss the recent strategies to improve gold nanorod-assisted photothermal therapy through combination with chemotherapy and photodynamic therapy.
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