Cortactin: an Achilles' heel of the actin cytoskeleton targeted by pathogens

Cortactin is an actin-binding protein and a central regulator of the actin cytoskeleton. Importantly, cortactin is also a common target exploited by microbes during infection. Its involvement in disease development is exemplified by a variety of pathogenic processes, such as pedestal formation [enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC)], invasion (Shigella, Neisseria, Rickettsia, Chlamydia, Staphylococcus and Cryptosporidium), actin-based motility (Listeria, Shigella and vaccinia virus) and cell scattering (Helicobacter). Recent progress turns our attention to how cortactin function can be regulated by serine and tyrosine phosphorylation. This has an important impact on how pathogens abuse cortactin to modulate the architecture of the host actin cytoskeleton.     

Exposing plasmids as the Achilles' heel of drug-resistant bacteria

Many multidrug-resistant bacterial pathogens harbor large plasmids that encode proteins conferring resistance to antibiotics. Although the acquisition of these plasmids often enables bacteria to survive in the presence of antibiotics, it is possible that plasmids also represent a vulnerability that can be exploited in tailored antibacterial therapy. This review highlights three recently described strategies designed to specifically combat bacteria harboring such plasmids: inhibition of plasmid conjugation, inhibition of plasmid replication, and exploitation of plasmid-encoded toxin-antitoxin systems.     

Targeting the cancer initiating cell: the Achilles' heel of cancer

We have isolated cell with the cancer initiating cell (CIC) phenotype from PC3 cells. The PC3/(CIC) cells are more resistant than the PC3/(BC) cells to chemotherapeutic drugs such as docetaxel which is used to treat prostate cancer. Thus these prostate CICs could lay dormant and persist even after chemotherapeutic drug treatment. Then when the chemotherapeutic drug is removed, they could potentially repopulate the original tumor site or metastize to a distant site. However, the prostate CICs were not significantly more resistant to drugs which target EGFR, NF-κB, Smo and the natural product genistein. Interesting the prostate CICs could be rendered more sensitive to docetaxel by inclusion of suboptimal doses of genistein, cyclopamine, and EGFR inhibitors. In contrast, addition of suboptimal amounts of genistein, cyclopamine, or EGFR inhibitors did not increase the sensitivity of the PC/(BC) cells to docetaxel. Similar results were observed when combination experiments were performed with cyclopamine and suboptimal doses of either genistein or docetaxel. The BC cells are usually more rapidly proliferating than the CICs. Thus the CICs are not as sensitive to docetaxel which targets replication. In contrast, the CICs could be rendered sensitive to docetaxel or cyclopamine by co-treatment with certain other drugs, including the natural product genistein which is present in the human diet of many people, especially Asians. Genistein is by itself only weakly toxic to prostate and other cancer cells. That is probably one of the big reasons that it can be used as a dietary supplement for prostate and breast cancers. It is clear from our studies that low doses of genistein can increase the sensitivity of prostate CICs to drugs such as docetaxel and cyclopamine, two drugs either used or under consideration for prostate cancer therapy.     

Cytoskeletal transition at the paranodes: the Achilles' heel of myelinated axons

Myelination organizes axons into distinct domains that allow nerve impulses to propagate in a saltatory manner. The edges of the myelin sheath are sealed at the paranodes by axon-glial junctions that have a crucial role in organizing the axonal cytoskeleton. Here we propose a model in which the myelinated axons depend on the axon-glial junctions to stabilize the cytoskeletal transition at the paranodes. Thus paranodal regions are likely to be particularly susceptible to damage induced by demyelinating diseases such as multiple sclerosis.     

Surgery and stem cell niches: An Achilles' heel of metastatic cancer

According to a classic paradigm, surgery only plays a palliative role in patients with metastatic cancer in whom the possibility of a radical resection is non-viable. However, some convincing data proceeding from two randomized trials carried out in patients with metastatic kidney cancer have challenged this assumption. The hypothesis proposes that the resection of the primary tumour in metastatic cancer is the first generation of forthcoming therapies aiming at stem cell niches. It will independently improve the prognosis of metastatic cancer in patients that are fit enough to tolerate major surgery. The phenomenon of late relapses could also be explained on this basis.     

Fast, hungry and unstable: finding the Achilles' heel of small-cell lung cancer

Over 95% of patients with small-cell lung cancer (SCLC) die within five years of diagnosis. The standard of care and the dismal prognosis for this disease have not changed significantly over the past 25 years. Some of the characteristics of SCLC that have defined it as a particularly virulent form of cancer -- rapid proliferation, excessive metabolic and angiogenic dependence, apoptotic imbalance and genetic instability -- are now being pursued as tumor-specific targets for intervention both in preclinical and early phase clinical studies. Here, we summarize areas of ongoing anti-cancer drug development, including classes of agents that target essential pathways regulating proliferation, angiogenesis, apoptotic resistance, chromosomal and protein stability, and cell-cell and cell-matrix interaction.     

Odor-based recognition of nectar in cursorial spiders

Carnivorous arthropods are known to rely on non‐prey foods, such as honeydew, pollen, and nectar. Consumption of plant‐based nutrients by spiders also appears to be widespread, especially in cursorial species. This is not surprising, as studies have shown that these spiders’ activity levels, survivorship, and reproduction are increased when their diet includes plant‐based nutrients, especially under conditions of prey scarcity. However, the sensory and behavioral means by which they recognize and locate non‐prey food is unknown. Here we show that immatures of a nectarivorous spider [Hibana futilis Banks (Araneae: Anyphaenidae)] can recognize and remember particular chemical stimuli associated with nectar. Following ingestion of minute amounts of sugar, these spiders exhibited counterturning and other local searching behaviors that increased their chances of finding more nectar. When placed on test arenas, spiders that were naïve with respect to nectar aroma located artificial nectaries composed of diluted honey significantly faster than unscented nectaries composed of 1 m sucrose solution. These results indicate that H. futilis is neurophysiologically and behaviorally adapted for recognizing olfactory stimuli. Interestingly, only spiders that ingested sugar and were engaged in local search responded to nectar aroma, suggesting that stimulation into local search is necessary to prime olfactory responses. We found that H. futilis could be conditioned to associate the presence of nectar with a novel aroma, in this case vanilla, and remember this aroma over the course of several hours. In arenas with vanilla‐scented nectaries, spiders that had previous experience feeding on vanilla‐scented sucrose droplets located the nectaries significantly faster than did vanilla‐naïve spiders. The capacity to remember specific aromas could enhance the spiders’ ability to find nectar, either when moving between different parts of the same plant or among different plant species. The results here indicate that nectarivorous spiders possess the sensory capabilities and programed behaviors necessary for efficient detection, recognition, and location of nectar sources.     

Lessons learned from testicular cancer: Identification of cytoplasmic p21 as an Achilles' heel of cisplatin resistance

Comment on: Koster R, et al. J Clin Invest 2010; 120:3594-605; DOI:10.1172/JCI41939.     

Visual control of cursorial prey pursuit by tiger beetles (Cicindelidae)

Target detection poses problems for moving animals, such as tiger beetles, that track targets visually. The pursuer's movements degrade target image contrast and induce reafferent image movement that confounds continuous detection of prey. In nature, beetles pursue prey discontinuously with several iterations of stop-and-go running. The beetle's dynamics were analyzed by filming pursuits of prey or experimenter-controlled dummies. Durations of stops are inversely related to prey visual angular velocity; as the prey image moves between neighboring ommatidial fields, the beetle relocalizes it and renews running. During subsequent runs, translation and rotation depend upon prey visual angular velocity and position, respectively, seen during the previous stop. The beetle runs, then stops, while prey continues moving. After two to three iterations of stop-and-go the beetle catches its prey, suggesting open-loop control of running. Computational model simulations produce good qualitative spatio-temporal fit with actual pursuits. However, when pursuing prey dummies, beetles track continuously and quickly follow changes in target position, suggesting closed-loop control using a position-sensitive servo mechanism. Differences between these types of pursuit control system are discussed with respect to limitations in signal detection, particularly spatio-temporal contrast, that may force beetles to use an open-loop system. Accepted: 7 April 1997     

Achilles' heel cleavage: creation of rare restriction sites in lambda phage genomes and evaluation of additional operators, repressors and restriction/modification systems

A novel technique for the creation of rare restriction sites was described by Koob et al. [Science 241 (1988) 1084-1086]. This technique, Achilles' heel cleavage (AC), relies on the use of a bound repressor molecule to protect only one of many identical restriction sites from a modification methyltransferase that inactivates all other restriction sites. The technique was applied to a small plasmid and shown to work efficiently with two repressor/operator systems: lac repressor/lacO operator and lambda repressor/lambda oL1 operator. Here, we have extended these results to a lac operator carried by a much larger vector, namely a 44-kb phage lambda construct. In addition, we have evaluated the effect of altering the stability of the lac repressor/lac operator complex by varying both the operator and the repressor. We have also evaluated several more restriction/modification systems (MboI, Dam, MspI and AluI) in addition to HhaI and HaeII used earlier. Finally, we extended the AC technique to a third system, that of the phage 434 repressor and a synthetic 434 operator. From our results we conclude that the AC method should be applicable to the mapping of large genomes and to measuring the strength of operator-repressor interactions. AC could also be applied to identifying and evaluating many different DNA-binding proteins and their sites of action.     

Habitat preferences of ptarmigan hunters in Norway

Hunting for willow ptarmigan (Lagopus lagopus) is a popular recreational activity in Norway, but studies of the hunters are limited. While large game management in Norway is based on sound models and research, management of small game hunters and hunting have not been subject to the same rigour. Compared to the extensive body of knowledge about ptarmigan behaviour and habitat preferences, the knowledge base on ptarmigan hunters is very limited. We surveyed the habitat preferences of 3,056 hunters to identify preferred landscape categories using pictures covering a range of landscape types. We also examined to which extent residence types and forms of hunting were related to habitat preferences. Through factor analysis, we identified three categories of hunting habitat; mountain forest, low alpine and high alpine. Mode of hunting is more important than residence status in terms of preferred habitat. Hunters using dogs preferred mountain forest and low alpine habitats more than hunters without dogs. Hunters without dogs had a higher preference than dog hunters for high alpine habitats. Hunters with mixed modes of hunting have wider habitat preferences. Residence status only affects the perception of the mountain forest habitat. The results may have implications for management as land use and place-based meanings are currently changing in many natural and rural landscapes, and hunting needs to be integrated with other recreational uses.     

Physiological Achilles' heels of enteropathogenic bacteria in livestock

An elaborate feeding regimen of animals, which takes advantage of the Achilles' heels of enteropathogenic bacteria, can possibly enable prophylaxis in the intestinal tract, attenuate actual disease symptoms, accelerate recovery from a bacterial gastroenteritis or ensure food safety. There is a wide spectrum of conceivable weak spots in bacteria. Some pathogenic bacteria cannot use certain compounds, or use them less efficient than beneficial bacteria. By addition of such substances to animal feed, non-pathogenic bacteria can grow better than pathogens and competitively exclude the latter ones. Other compounds even have an inhibitory effect on pathogens. Calcium phosphate for example protects against Salmonella, Zn2+ has a prophylactic effect against Brachyspira, and Fe2+ has an inhibiting effect on the enterotoxin synthesis of Yersinia enterocolitica. Besides, there are antimicrobial substances as plant extracts, essential oils, organic acids and other compounds, which inhibit pathogens more than other bacteria. A simultaneous application of several anti-pathogen agents suggest an enhanced effect. Some countermeasures aim at a distinct group of bacteria, while others are more universal. General strategies to repel different pathogenic bacteria are the supply of health-stimulating milk components, antagonistic bacteria for competitive exclusion, and mucus-related attractants for misguidance of adhering and invasive bacteria. This paper gives an overview of Achilles' heels of enteropathogenic bacteria that can be exploited to develop strategies for keeping control over these pathogens in the gastrointestinal tract of livestock.     

Bipedal locomotion in ratites (Paleognatiform): examples of cursorial birds

The gaits of five Ostriches Struthio camelus , seven Emus Dromaius novaehollandiae, two Greater Rheas Rhea americana, two Southern Cassowaries Casuarius casuarius and one Brown kiwi Apteryx australis were filmed at zoological parks. Locomotor parameters were measured using footprints on sandy tracks and video records. Osteological measurements were made on skeletons of the pelvic limbs. All of these terrestrial birds shift from wallking to running at a relative speed below 1. However, they show two different locomotor patterns: the Brown Kiwi increases its speed by increasing its stride length, mainly by increasing the protraction angle. Its hindlimbs make a flexed jointed chain system, its centre of mass is anterior, its femurs are long and the knees act in yield whereas the distal joints act in propulsion. Other ratites, particularly Ostriches, increase their speed by increasing frequency. Their centre of mass is close to the hip, their hindlimbs have an extended jointed chain system with a short erect femur, maximizing a gravity-powered system.     

The socioecology of fission-fusion sociality in Orangutans

Fission-fusion systems can have the group or the individual as their primary unit. In group-based fission-fusion systems, predation risk reduction is the major benefit to grouping, in the individual-based ones the benefits are likely to be primarily social. Orangutans, like chimpanzees, are examples of an individual-based fission-fusion species. The orangutans inhabiting a Sumatran swamp forest (Suaq Balimbing) are more likely than elsewhere to form travel parties. As elsewhere, the main benefits of grouping are social: mating opportunities, protection from harassment and socialization of infants. Most animals also incur costs, but these are relatively low at Suaq Balimbing due to the high productivity of the swamp. Costs seem to be disproportionately high for females with mid-sized infants, who avoid parties.