Delayed ageing through damage protection by the Arf/p53 pathway

The tumour-suppressor pathway formed by the alternative reading frame protein of the Cdkn2a locus (Arf) and by p53 (also called Trp53) plays a central part in the detection and elimination of cellular damage, and this constitutes the basis of its potent cancer protection activity. Similar to cancer, ageing also results from the accumulation of damage and, therefore, we have reasoned that Arf/p53 could have anti-ageing activity by alleviating the load of age-associated damage. Here we show that genetically manipulated mice with increased, but otherwise normally regulated, levels of Arf and p53 present strong cancer resistance and have decreased levels of ageing-associated damage. These observations extend the protective role of Arf/p53 to ageing, revealing a previously unknown anti-ageing mechanism and providing a rationale for the co-evolution of cancer resistance and longevity.     

Probing the chemistry of thioredoxin catalysis with force

Thioredoxins are enzymes that catalyse disulphide bond reduction in all living organisms. Although catalysis is thought to proceed through a substitution nucleophilic bimolecular (S(N)2) reaction, the role of the enzyme in modulating this chemical reaction is unknown. Here, using single-molecule force-clamp spectroscopy, we investigate the catalytic mechanism of Escherichia coli thioredoxin (Trx). We applied mechanical force in the range of 25-600 pN to a disulphide bond substrate and monitored the reduction of these bonds by individual enzymes. We detected two alternative forms of the catalytic reaction, the first requiring a reorientation of the substrate disulphide bond, causing a shortening of the substrate polypeptide by 0.79 +/- 0.09 A (+/- s.e.m.), and the second elongating the substrate disulphide bond by 0.17 +/- 0.02 A (+/- s.e.m.). These results support the view that the Trx active site regulates the geometry of the participating sulphur atoms with sub-?ngstr?m precision to achieve efficient catalysis. Our results indicate that substrate conformational changes may be important in the regulation of Trx activity under conditions of oxidative stress and mechanical injury, such as those experienced in cardiovascular disease. Furthermore, single-molecule atomic force microscopy techniques, as shown here, can probe dynamic rearrangements within an enzyme's active site during catalysis that cannot be resolved with any other current structural biological technique.     

Human endoglin as a potential new partner involved in platelet–endothelium interactions

Complex interactions between platelets and activated endothelium occur during the thrombo-inflammatory reaction at sites of vascular injuries and during vascular hemostasis. The endothelial receptor endoglin is involved in inflammation through integrin-mediated leukocyte adhesion and transmigration; and heterozygous mutations in the endoglin gene cause hereditary hemorrhagic telangiectasia type 1. This vascular disease is characterized by a bleeding tendency that is postulated to be a consequence of telangiectasia fragility rather than a platelet defect, since platelets display normal functions in vitro in this condition. Here, we hypothesize that endoglin may act as an adhesion molecule involved in the interaction between endothelial cells and platelets through integrin recognition. We find that the extracellular domain of human endoglin promotes specific platelet adhesion under static conditions and confers resistance of adherent platelets to detachment upon exposure to flow. Also, platelets adhere to confluent endothelial cells in an endoglin-mediated process. Remarkably, Chinese hamster ovary cells ectopically expressing the human αIIbβ3 integrin acquire the capacity to adhere to myoblast transfectants expressing human endoglin, whereas platelets from Glanzmann’s thrombasthenia patients lacking the αIIbβ3 integrin are defective for endoglin-dependent adhesion to endothelial cells. Furthermore, the bleeding time, but not the prothrombin time, is significantly prolonged in endoglin-haplodeficient (Eng ^+/?) mice compared to Eng ^+/+ animals. These results suggest a new role for endoglin in αIIbβ3 integrin-mediated adhesion of platelets to the endothelium, and may provide a better understanding on the basic cellular mechanisms involved in hemostasis and thrombo-inflammatory events.     

Adamantinomatous craniopharyngioma as a model to understand paracrine and senescence-induced tumourigenesis

Cellular and Molecular Life Sciences - Cellular senescence is a process that can prevent tumour development in a cell autonomous manner by imposing a stable cell cycle arrest after oncogene...     

Tedania (Porifera: Demospongiae: Poecilosclerida) from the Mexican Pacific with the description of two new species

Two new species of Tedania (Porifera: Demospongiae: Poecilosclerida) are described from the Mexican Pacific. Tedania (Tedania) tropicalis sp. nov. is an encrusting to massive sponge having ectosomal tylotes with microspined heads, choanosomal styles and onychaetes. Tedania (Tedania) fulvum sp. nov. is a thinly encrusting sponge having ectosomal tylotes with smooth heads, choanosomal styles and onychaetes. Tables for all the Tedania (subgenera Tedania and Tedaniopsis) and Trachytedania species described worldwide are included. We suggest that species of Tedania and Trachytedania bearing ectosomal diactinal spicules (excluding Tedania (Stylotedania)) can be separated in two main groups: those having choanosomal monactinal spicules and those with choanosomal diactinal spicules.

www.zoobank.org/urn:lsid:zoobank.org:pub:5B212DC3-3827-44D5-8E63-3E652BCB29E6     

Systematic identification of genomic markers of drug sensitivity in cancer cells

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.     

Human gut microbiome viewed across age and geography

Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ among human populations, here we characterize bacterial species in fecal samples from 531 individuals, plus the gene content of 110 of them. The cohort encompassed healthy children and adults from the Amazonas of Venezuela, rural Malawi and US metropolitan areas and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial assemblages and functional gene repertoires were noted between US residents and those in the other two countries. These distinctive features are evident in early infancy as well as adulthood. Our findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations and the impact of westernization.     

Design and Analysis of Prioritized Medium Access Control Protocol for Backbone Routers in Wireless Mesh Networks

A Prioritized Medium Access Control (P-MAC) protocol is proposed for wireless routers of mesh networks with quality-of-service provisioning. The simple yet effective design of P-MAC offers strict service differentiation for prioritized packets. A Markov model is developed to yield important performance matrices including the packet blocking probability due to queue overflow and the packet reneging probability due to delay bound. It is further proved that the service time of P-MAC approximates exponential distribution, and can be effectively estimated. The analytic models with preemptive and non-preemptive schemes, validated via simulations, show that P-MAC can effectively support traffic differentiation and achieve very low packet dropping (both reneging and blocking) probabilities when the traffic load is below the channel capacity. When the network is overloaded, P-MAC can still maintain extremely stable and high channel throughput. Moreover, it is demonstrated that P-MAC performs superior in multihop networks, further proving the advantages of the proposed protocol.