Target insensitivity

Insensitive munitions are munitions which are stable enough to withstand mechanical shocks, fire, and impact by shrapnel, but that are still able to explode as intended in order to destroy their targets. Insensitive munitions will only bum (rather than explode) when subjected to fast or slow heating, bullets, shrapnel, shaped charges, or the detonation of another nearby munition. The term typically refers to warheads, bombs, and rocket motors. Insensitive munitions are munitions that are less sensitive to unplanned stimuli that might cause unplanned ignition of the munition. 

Resistance can also arise when target enzymes, ie, the PBPs, and in particular the transpeptidases, are modified. Target-mediated cephalosporin resistance can involve either a reduced affinity for an existing PBP, or the acquisition of a supplementary, P-lactam insensitive PBP (139). 

Compared to other spectroscopic methods, NMR spectroscopy is a very insensitive technique. As a general rule of thumb, the sample studied must contain at least 10 moles of target nuclei. The required sample size thus depends on the percentage of the element present in the sample, as well as on the natural abundance of the... 

Resistance to DDT has been developed in many insect species. Although there are some cases of metabolic resistance (e.g., strains high in DDT dehydrochlorinase activity), particular interest has been focused on kdr and super kdr mechanisms based upon aberrant forms of the sodium channel—the principal target for DDT. There are many examples of insects developing resistance to dieldrin. The best-known mechanism is the production of mutant forms of the target site (GABA receptor), which are insensitive to the insecticide. 

Indeed, the resistance problem has sometimes been severe enough to threaten a loss of control over the pest. A study of a number of resistant strains from the field has revealed two major types of resistance mechanism. Some individuals possess aberrant forms of the target site, the Na" channel. At least two forms are known that confer either kdr (<100-fold) or super kdr (>100-fold) resistance, which is the consequence of the presence of insensitive forms of the Na+ channel protein (McCaffery 1998, and Chapter 4, Section 4.4 of this book). 

With respect to toxins which target specific sites, insight can be obtained from the anomolies that are observed. For example, both puffer fish and tetrodotoxin-containing crabs (96) are insensitive to tetrodotoxin. The investigation of such insensitivities can provide information about membrane channels and their toxin binding sites. 

The processes of both seed formation and fibril extension are dependent on temperature and on peptide concentration, with 37°C being required for establishing equilibrium within 24 h with 30 pM Pi 4o- A full description of the assay system may be found elsewhere [97,117], A 4 h reaction time is typically within the linear portion of the time course. This nucleus-dependent assay detects mainly inhibitors that are substoichiometric with the monomeric peptide, which is present at high concentration. It is relatively insensitive to inhibitors that target the monomeric peptide. Whether the inhibitors interact with the growing end of a seed or with a low abundance conformational form of the p peptide that is competent to add to the seed is difficult to determine at this time. Similar dose-response curves are obtained for Congo Red as an inhibitor with either thioflavin T (ThT) fluorescence or filtration of radioiodinated peptide readouts (Fig. 4) Caveats in the interpretation of both the ThT and radiometric filtration assays for the evaluation of putative inhibitors are discussed elsewhere [97]. 

In natural circumstances, at least one individual in 10,000 carries an unusual mutation, which, if fixed by selection, may turn into a new characteristic. Insensitivity to a chemical substance that has not been seen over millions of years of evolution is a rare characteristic, and the frequency of such mutations is not 104, but closer to 107 or even 109. If there are over one billion individuals in the population of the target species, then less sensitive members will always be present in the first generation. They will survive, and will have progeny. Three to four generations later, the population of the target species will be the same size as, or even larger than, it was before pesticide use however, the majority of individuals will be less sensitive to the pesticide. 

In contrast to that of reporting dye, the reference emission should be completely insensitive to the presence of target. 

NGF has effects on the physiological responses of mature neurons. NGF acts as a target-derived trophic factor for pain neurons, which innervate peripheral tissues such as the skin. Inflammation of these peripheral tissues leads to local elevation of NGF synthesis and abundance. Elevated concentartions of NGF are responsible for the enhanced sensitivity to pain that accompanies inflammation. This is due to the ability of NGF to lower the sensory threshold of the pain fibers, leading to hyperalgesia. Nocioceptive sensory neurons mediating pain sensation are entirely dependent upon NGF for their survival as these cells are selectively lost in animal in which either the NGF or TrkA genes have been knocked out. These animals are insensitive to pain and live only a few weeks. 

Gunther, U., Benson, J., Benke, D et al. (1995) Benzodiazepine-insensitive mice generated by targeted disruption of the y2-subunit gene of y-aminobutyric acid type A receptors. Proc. Natl. Acad. Sci. USA 92,7749-7753. 

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