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Appropriate Targets (appropriate + target)
Selected AbstractsInsulin resistance and fuel homeostasis: the role of AMP-activated protein kinaseACTA PHYSIOLOGICA, Issue 1 2009B. D. Hegarty Abstract The worldwide prevalence of type 2 diabetes (T2D) and related disorders of the metabolic syndrome (MS) has reached epidemic proportions. Insulin resistance (IR) is a major perturbation that characterizes these disorders. Extra-adipose accumulation of lipid, particularly within the liver and skeletal muscle, is closely linked with the development of IR. The AMP-activated protein kinase (AMPK) pathway plays an important role in the regulation of both lipid and glucose metabolism. Through its effects to increase fatty acid oxidation and inhibit lipogenesis, AMPK activity in the liver and skeletal muscle could be expected to ameliorate lipid accumulation and associated IR in these tissues. In addition, AMPK promotes glucose uptake into skeletal muscle and suppresses glucose output from the liver via insulin-independent mechanisms. These characteristics make AMPK a highly attractive target for the development of strategies to curb the prevalence and costs of T2D. Recent insights into the regulation of AMPK and mechanisms by which it modulates fuel metabolism in liver and skeletal muscle are discussed here. In addition, we consider the arguments for and against the hypothesis that dysfunctional AMPK contributes to IR. Finally we review studies which assess AMPK as an appropriate target for the prevention and treatment of T2D and MS. [source] Initial stages of neural regeneration in Helisoma trivolvis are dependent upon PLA2 activityDEVELOPMENTAL NEUROBIOLOGY, Issue 4 2003Matthew S. Geddis Abstract Neuronal regeneration after damage to an axon tract requires the rapid sealing of the injured plasma membrane and the subsequent formation of growth cones that can lead regenerating processes to their appropriate target. Membrane sealing and growth cone formation are Ca2+ -dependent processes, but the signaling pathways activated by Ca2+ to bring about these effects remain poorly understood. An in vitro injury model was employed in which neurites from identified snail neurons (Helisoma trivolvis) were transected with a glass microknife, and the formation of new growth cones from the distal portions of transected neurites was recorded at defined times after transection. This study presents three main results. First, phospholipase A2 (PLA2), a calcium-activated enzyme, is necessary for membrane sealing in vitro. Second, PLA2 activity is also required for the formation of a new growth cone after the membrane has sealed successfully. Thus, PLA2 plays a dual role by affecting both growth cone formation and membrane sealing. Third, the injury-induced activation of PLA2 by Ca2+ controls growth cone formation through the production of leukotrienes, secondary metabolites of PLA2 activity. Taken together, these results suggest that the injury-induced Ca2+ influx acts via PLA2 and leukotriene production to assure growth cone formation. These findings indicate that events that cause an inhibition of PLA2 or lipoxygenases, enzymes that produce leukotrienes, could result in the inability of neurites to regenerate. © 2003 Wiley Periodicals, Inc. J Neurobiol 54: 555,565, 2003 [source] Spectral shape, epsilon and record selectionEARTHQUAKE ENGINEERING AND STRUCTURAL DYNAMICS, Issue 9 2006Jack W. Baker Abstract Selection of earthquake ground motions is considered with the goal of accurately estimating the response of a structure at a specified ground motion intensity, as measured by spectral acceleration at the first-mode period of the structure, Sa(T1). Consideration is given to the magnitude, distance and epsilon (,) values of ground motions. First, it is seen that selecting records based on their , values is more effective than selecting records based on magnitude and distance. Second, a method is discussed for finding the conditional response spectrum of a ground motion, given a level of Sa(T1) and its associated mean (disaggregation-based) causal magnitude, distance and , value. Records can then be selected to match the mean of this target spectrum, and the same benefits are achieved as when records are selected based on ,. This mean target spectrum differs from a Uniform Hazard Spectrum, and it is argued that this new spectrum is a more appropriate target for record selection. When properly selecting records based on either spectral shape or ,, the reductions in bias and variance of resulting structural response estimates are comparable to the reductions achieved by using a vector-valued measure of earthquake intensity. Copyright © 2006 John Wiley & Sons, Ltd. [source] Theories of drug craving, ancient and modernADDICTION, Issue 1 2001D. Colin Drummond This paper reviews the principal theoretical models of drug craving and provides some directions for future research. The main models are classified broadly into three categories: (1) phenomenological models; based on clinical observation and description; these have been influential in classification systems of addictive disorders and in the development of pharmacological therapies; (2) conditioning models: based on conditioning theory; these have been influential in the development of cue exposure treatments; (3) cognitive theories; based on cognitive social learning theory: these have been influential in the development of cognitive therapies of addiction. It is concluded that no one specific theory provides a complete explanation of the phenomenon of craving. However, theories of craving grounded in general theories of human behaviour offer greatest promise, and generate more specific and testable research hypotheses. Theories that do not require craving to be present for relapse to occur have more empirical support than those that provide simplistic causal explanations. The cue-reactivity model shows promise in the exploration of the relationship between craving and relapse. However, further attention to the phenomenology of craving could help to advise the future measurement and study of drug craving, particularly in the context of research in which drugs are available to human subjects, with adequate ethical safeguards. There is a need for further study of the temporal dynamics of craving and consensus in the field on the most appropriate methods of measurement. Finally, new psychotherapies such as cue exposure and pharmacotherapies that aim to attenuate drinking behaviour, such as naltrexone and acamprosate, provide opportunities to improve understanding of the nature and significance of craving. However, the relatively uncritical assumption that craving is the underlying basis of addiction and represents the most appropriate target for treatment is challenged. [source] Fibrosis in heart disease: understanding the role of transforming growth factor-,1 in cardiomyopathy, valvular disease and arrhythmiaIMMUNOLOGY, Issue 1 2006Razi Khan Summary The importance of fibrosis in organ pathology and dysfunction appears to be increasingly relevant to a variety of distinct diseases. In particular, a number of different cardiac pathologies seem to be caused by a common fibrotic process. Within the heart, this fibrosis is thought to be partially mediated by transforming growth factor-,1 (TGF-,1), a potent stimulator of collagen-producing cardiac fibroblasts. Previously, TGF-,1 had been implicated solely as a modulator of the myocardial remodelling seen after infarction. However, recent studies indicate that dilated, ischaemic and hypertrophic cardiomyopathies are all associated with raised levels of TGF-,1. In fact, the pathogenic effects of TGF-,1 have now been suggested to play a major role in valvular disease and arrhythmia, particularly atrial fibrillation. Thus far, medical therapy targeting TGF-,1 has shown promise in a multitude of heart diseases. These therapies provide great hope, not only for treatment of symptoms but also for prevention of cardiac pathology as well. As is stated in the introduction, most reviews have focused on the effects of cytokines in remodelling after myocardial infarction. This article attempts to underline the significance of TGF-,1 not only in the post-ischaemic setting, but also in dilated and hypertrophic cardiomyopathies, valvular diseases and arrhythmias (focusing on atrial fibrillation). It also aims to show that TGF-,1 is an appropriate target for therapy in a variety of cardiovascular diseases. [source] Target-dependent modulation of neurotransmitter release in cultured Helix neurons involves adhesion moleculesJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2001Mirella Ghirardi Abstract The secretory capabilities of the serotonergic neuron C1 of cerebral ganglion of Helix pomatia were markedly reduced when it was cultured in contact with the wrong target neuron, C3. When the neuron B2, one of its physiological targets, was micromanipulated within the network made of intermingled neurites originating from the axonal stumps of both C1 and C3 neurons, C1 increased the amount of the evoked transmitter release, which, after 30 min, reached the level observed when cocultured with the appropriate target. The removal of the appropriate target brought C1 back to the low release condition. By imaging C1 neurites with a fluorescent dye, morphological changes involving a local increase in the number of varicosities could be observed as early as 30 min after contact with the appropriate target. Monoclonal antibody 4E8 against apCAM, a family of Aplysia adhesion molecules, recognizes apCAM-like molecules of the Helix central nervous system on immunocytochemistry and Western blot analysis. The contact with the appropriate target previously incubated in a 4E8 solution, which did not interfere with its capacity to respond to serotonin, failed to increase the transmitter release of C1 cocultured in the presence of the wrong target, C3. These results suggest that the apCAM-like antigens bound to the target membrane participate in the molecular processes responsible for the assembly of the "release machinery" present in the functional presynaptic structure. J. Neurosci. Res. 65:111,120, 2001. © 2001 Wiley-Liss, Inc. [source] Defective Jak,Stat activation in renal cell carcinoma is associated with interferon-, resistanceCANCER SCIENCE, Issue 8 2007Donghao Shang Chemotherapy is ineffective against metastatic renal cell carcinoma (RCC). Interferon (IFN)-, has become the most common agent used in clinical therapy to overcome this malignant tumor, although a satisfactory response has not been achieved and the mechanism of resistance of RCC to IFN-, remains unclear. The purpose of the present study was to evaluate the susceptibility of RCC cells to IFN-, and clarify the mechanism of IFN-, resistance in RCC. Six RCC cell lines and three types of IFN-, were used, and the expression, activation and effects of transfection of possible proteins or factors reported to be involved in IFN-, signaling were examined to clarify the mechanism of resistance. The results suggest that the resistance of RCC to IFN-, is associated with the lack of Jak1, Tyk2 and Stat1 expression and defective Jak,Stat activation, but not with a lack of IFN-, receptor, suppressors of cytokine signaling induction or other factors examined. Moreover, phosphorylation of Jak,Stat pathway components and reversion of IFN-, resistance in RCC were observed upon transfection with Jak1, Tyk2 or Stat1 vector. These results suggest that restoring the expression of Jak or Stat1 might strikingly increase the susceptibility of RCC to IFN-, and may be a new strategy for improving the response of RCC to IFN-, treatment. The Jak,Stat pathway should therefore be an appropriate target for the treatment of RCC. (Cancer Sci 2007; 98: 1259,1264) [source] Vascular endothelial growth factor receptor-2: Its unique signaling and specific ligand, VEGF-ECANCER SCIENCE, Issue 9 2003Masabumi Shibuya Vascular endothelial growth factor receptor-2 (VEGFR-2/KDR/Flk-1) is a high-affinity receptor for vascular endothelial growth factor-A (VEGF-A), and mediates most of the endothelial growth and survival signals from VEGF-A. VEGFR-2 has a typical tyrosine kinase receptor structure with seven immunoglobulin (Ig)-like domains in the extracellular region, as well as a long kinase insert in the tyrosine kinase domain. It utilizes a unique signaling system for DNA synthesis in vascular endothelial cells, i.e. a phospholipase C,-protein kinaseC-Raf-MAP kinase pathway. Although VEGF-A binds two receptors, VEGFR-1 and -2, a newly isolated ligand VEGF-E (Orf-virus-derived VEGF) binds and activates only VEGFR-2. Transgenic mice expressing VEGF-ENZ-7 showed a dramatic increase in angiogenesis with very few side effects (such as edema and hemorrhagic spots), suggesting strong angiogenic signaling and a potential clinical utility of VEGF-E. VEGF family members bear three loops produced via three intramolecular disulfide bonds, and cooperation between loop-1 and loop-3 is necessary for the specific binding and activation of VEGFR-2 for angiogenesis. As it directly upregulates tumor angiogenesis, VEGFR-2 is an appropriate target for suppression of solid tumor growth using exogenous antibodies, small inhibitory molecules and in vivo stimulation of the immune system. [source] Findings from a multidisciplinary clinical case series of females with Rett syndromeDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 5 2003Hilary Cass BSc FRCPCH Systematic data from a multidisciplinary clinical assessment of a large series of females with Rett syndrome (RS; n=87) is presented. Participants' ages ranged from 2 years 1 month to 44 years 10 months. Areas assessed included oromotor skills, feeding problems, growth, breathing abnormalities, mobility, postural abnormalities and joint deformities, epilepsy, hand use and stereotypies, self-care, and cognitive and communication skills. Many previously reported trends in the presentation of RS over time were confirmed, notably the increasingly poor growth and near pervasiveness of fixed joint deformities and scoliosis in adulthood. In contrast, there was a slight trend towards improved autonomic function in adulthood, whereas feeding difficulties increased into middle childhood and then reached a plateau. Improvements in mobility into adolescence were followed by a decline in those skills in adulthood. Levels of dependency were high, confirming findings from previous studies. Despite the presence of repetitive hand movements, a range of hand-use skills was seen in individuals of all ages. Cognitive and communication skills were limited, but there was little evidence of deterioration of these abilities with age. These findings confirm that RS is not a degenerative condition and indicate that intervention and support to maintain and increase motor skills, daily living skills, and cognitive and communicative functioning are appropriate targets for individuals with RS. [source] Population and Species Divergence of Chemical Cues that Influence Male Recognition of Females in Desmognathine SalamandersETHOLOGY, Issue 7 2003Paul Verrell Growing evidence indicates that males may be more discriminating of mating partners than often has been assumed. In the North American Ocoee dusky salamander, Desmognathus ocoee (Plethodontidae: Desmognathinae), sexual incompatibility among conspecific populations is high in encounters staged in the laboratory, at least in part because males fail to recognize ,other' females as appropriate targets for courtship. I used Y-mazes to test the hypothesis that males of D. ocoee discriminate between substrate-borne chemical cues produced by ,own' (homotypic) and ,other' (heterotypic) females. Males of four populations discriminated in favor of substrates soiled by homotypic females over clean (control) substrates (expt 1), suggesting that females produce chemical cues of sociosexual significance to males. Furthermore, males from these populations discriminated in favor of substrates soiled by homotypic females vs. substrates soiled by heterotypic females (expt 2), both conspecific and heterospecific (D. carolinensis and D. orestes). Thus, differences among populations and species in female chemical cues appear to affect the chemotactic responses of males. I suggest that, together with differences in behavioral signals and responses exhibited during courtship, differences in female chemical cues likely contribute to sexual incompatibility among populations and taxa of desmognathine salamanders. [source] BROADENING THE APPLICATION OF EVOLUTIONARILY BASED GENETIC PEST MANAGEMENTEVOLUTION, Issue 2 2008Fred Gould Insect- and tick-vectored diseases such as malaria, dengue fever, and Lyme disease cause human suffering, and current approaches for prevention are not adequate. Invasive plants and animals such as Scotch broom, zebra mussels, and gypsy moths continue to cause environmental damage and economic losses in agriculture and forestry. Rodents transmit diseases and cause major pre- and postharvest losses, especially in less affluent countries. Each of these problems might benefit from the developing field of Genetic Pest Management that is conceptually based on principles of evolutionary biology. This article briefly describes the history of this field, new molecular tools in this field, and potential applications of those tools. There will be a need for evolutionary biologists to interact with researchers and practitioners in a variety of other fields to determine the most appropriate targets for genetic pest management, the most appropriate methods for specific targets, and the potential of natural selection to diminish the effectiveness of genetic pest management. In addition to producing environmentally sustainable pest management solutions, research efforts in this area could lead to new insights about the evolution of selfish genetic elements in natural systems and will provide students with the opportunity to develop a more sophisticated understanding of the role of evolutionary biology in solving societal problems. [source] Where within a geographical range do species survive best?INSECT CONSERVATION AND DIVERSITY, Issue 1 2008A matter of scale Abstract., 1Opinions differ as to whether declining species are most likely to survive in central or peripheral parts of their distributions. The former pattern is likely to be driven by high extinction risks in peripheral areas; the latter by gradients of extinction risk. 2At a continental scale of analysis, the declining butterfly Euphydryas aurinia survived best in southern and eastern countries within Europe. This was statistically associated with geographical variation in agricultural intensification. At this scale of analysis, there was a gradient of survival, caused by a gradient of agricultural intensification. 3Within England and Wales, survival was greatest in population concentrations, or core areas; that is in 10-km grid squares that were surrounded by other 10-km grid squares that also contained populations of E. aurinia. In the English county of Dorset, populations were also most likely to be found in core areas; that is in habitat patches that were close to other populated habitat patches. 4In this system, there is support for two patterns of decline. At a coarse scale, there is a geographical gradient of habitat degradation, associated with agricultural intensification. But within a region where decline has taken place, populations survive best in core areas, where aggregations of habitat support viable metapopulation dynamics. 5Large-scale geographical patterns of decline towards the periphery (or other locations within) the distribution of a species do not negate the validity of conservation strategies based on core-margin population dynamic principles. Core areas within each country or region represent appropriate targets for conservation action. [source] Requesting patterns for serum calcium concentration in patients on long-term lithium therapyINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 1 2009B. J. Jones Summary Aim:, Long-term lithium therapy is associated with hypercalcaemia in 10,60% of patients, but unlike creatinine and thyroid stimulating hormone (TSH), monitoring by general practitioners of serum calcium for patients on lithium is not a requirement of the Qualities and Outcomes Framework (QOF) of 2004. We aimed to assess requesting patterns for serum calcium in patients on long-term lithium therapy and subsequent diagnosis of hypercalcaemia. Methods:, We identified 100 patients on long-term lithium therapy, as indicated by regular monitoring of lithium levels in our laboratory for at least 1 year. We determined how many of these patients had had serum calcium analysed, noting the assay date, concentration, source of request and clinical details stated. Results:, Forty-three out of hundred patients had serum calcium analysed during the course of their treatment including 28 in the previous 15 months. Twenty-one patients had serum calcium analysed by their GP, including 12 in the previous 15 months. Hypercalcaemia was diagnosed in five patients (11.6%). Conclusion:, A significant proportion of patients in whom calcium was checked developed hypercalcaemia on lithium therapy. However, only 12% of the patients had serum calcium requested by their GP in the previous 15 months, which compares unfavourably with TSH and creatinine, for which monitoring approaches 100%. We recommend that serum calcium be checked every 15 months along with creatinine and TSH. This might be achieved by incorporating appropriate targets into the QOF, or by reflective or reflex adding-on of calcium to lithium specimens from patients who have not had calcium analysed in the previous 15 months. [source] Seeking long-term relationship: axon and target communicate to organize synaptic differentiationJOURNAL OF NEUROCHEMISTRY, Issue 5 2006Michael A. Fox Abstract Synapses form after growing axons recognize their appropriate targets. The subsequent assembly of aligned pre and postsynaptic specializations is critical for synaptic function. This highly precise apposition of presynaptic elements (i.e. active zones) to postsynaptic specializations (i.e. neurotransmitter receptor clusters) strongly suggests that communication between the axon and target is required for synaptic differentiation. What trans-synaptic factors drive such differentiation at vertebrate synapses? First insights into the answers to this question came from studies at the neuromuscular junction (NMJ), where axon-derived agrin and muscle-derived laminin ,2 induce post and presynaptic differentiation, respectively. Recent work has suggested that axon- and target-derived factors similarly drive synaptic differentiation at central synapses. Specifically, WNT-7a, neuroligin, synaptic cell adhesion molecule (SynCAM) and fibroblast growth factor-22 (FGF-22) have all been identified as target-derived presynaptic organizers, whereas axon-derived neuronal activity regulated pentraxin (Narp), ephrinB and neurexin reciprocally co-ordinate postsynaptic differentiation. In addition to these axon- and target-derived inducers of synaptic differentiation, factors released from glial cells have also been implicated in regulating synapse assembly. Together, these recent findings have profoundly advanced our understanding of how precise appositions are established during vertebrate nervous system development. [source] Pyrethroid resistance/susceptibility and differential urban/rural distribution of Anopheles arabiensis and An. gambiae s.s. malaria vectors in Nigeria and GhanaMEDICAL AND VETERINARY ENTOMOLOGY, Issue 3 2003M. Kristan Abstract., Resistance to pyrethroid insecticides and DDT caused by the kdr gene in the malaria vector Anopheles gambiae Giles s.s. (Diptera: Culicidae) has been reported in several West African countries. To test for pyrethroid resistance in two more countries, we sampled populations of the An. gambiae complex from south-western Ghana and from urban and rural localities in Ogun State, south-west Nigeria. Adult mosquitoes, reared from field-collected larvae, were exposed to the WHO-recommended discriminating dosage of exposure for 1 h to DDT 4%, deltamethrin 0.05% or permethrin 0.75% and mortality was recorded 24 h post-exposure. Susceptibility of An. gambiae s.l. to DDT was 94,100% in Ghana and 72,100% in Nigeria, indicating low levels of DDT resistance. Deltamethrin gave the highest mortality rates: 97,100% in Ghana, 95,100% in Nigeria. Ghanaian samples of An. gambiae s.l. were fully susceptible to permethrin, whereas some resistance to permethrin was detected at 4/5 Nigerian localities (percentage mortalities 75, 82, 88, 90 and 100%), with survivors including both An. arabiensis Patton and An. gambiae s.s. identified by PCR assay. Even so, the mean knockdown time was not significantly different from a susceptible reference strain, indicating absence or low frequency of kdr -type resistance. Such low levels of pyrethroid resistance are unlikely to impair the effectiveness of pyrethroid-impregnated bednets against malaria transmission. Among Nigerian samples of An. gambiae s.l., the majority from two urban localities were identified as An. arabiensis, whereas the majority from rural localities were An. gambiae s.s. These findings are consistent with those of M. Coluzzi et al. (1979). Differences of ecological distribution between molecular forms of An. gambiae s.s. were also found, with rural samples almost exclusively of the S-form, whereas the M-form predominated in urban samples. It is suggested that ,urban island' populations of An. arabiensis and of An. gambiae s.s. M-form in the rainforest belt of West Africa might be appropriate targets for elimination of these malaria vectors by the sterile insect technique. [source] Vaccination as a Therapeutic Approach to Alzheimer's DiseaseMOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 1 2010Thomas Wisniewski MD Abstract Alzheimer's disease is the most common cause of dementia worldwide. Alzheimer's disease is a member of a broad range of neurodegenerative diseases characterized pathologically by the conformational change of a normal protein into a pathological conformer with a high ,-sheet content that renders it neurotoxic. In the case of Alzheimer's disease, the normal soluble amyloid , peptide is converted into oligomeric/fibrillar amyloid ,. The oligomeric forms of amyloid , have been hypothesized to be the most toxic, whereas fibrillar amyloid , becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat Alzheimer's disease. Among the most exciting and advanced of these approaches is vaccination. Immunomodulation is being tried for a range of neurodegenerative disorders, with great success being reported in most model animal trials; however, the much more limited human data have shown more modest clinical success so far, with encephalitis occurring in a minority of patients treated with active immunization. The immunomodulatory approaches for neurodegenerative diseases involve targeting a self-protein, albeit in an abnormal conformation; hence, effective enhanced clearance of the disease-associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation within the central nervous system. The design of future immunomodulatory approaches that are more focused is dependent on addressing a number of questions, including when is the best time to start immunization, what are the most appropriate targets for vaccination, and is amyloid central to the pathogenesis of Alzheimer's disease or is it critical to target tau-related pathology also. In this review, we discuss the past experience with vaccination for Alzheimer's disease and the development of possible future strategies that target both amyloid ,,related and tau-related pathologies. Mt Sinai J Med 77:17&–31, 2010. © 2010 Mount Sinai School of Medicine [source] Basal ganglia physiology and deep brain stimulation,MOVEMENT DISORDERS, Issue S1 2010Andres M. Lozano FRCSC Abstract Despite improvements in anatomic imaging of the basal ganglia, microelectrode recording is still an invaluable tool in locating appropriate targets for neurosurgical intervention. These recording also provide an unparalleled opportunity to study the pathophysiological aspects of diseases. This article reviews the principles of microelectrode recording in functional neurosurgery and discusses the pathologic neurophysiologic findings commonly encountered. It also highlights some of the potential mechanisms of action of both dopaminergic drugs and deep brain stimulation. In addition we review the recent work on pedunculopontine nucleus neurophysiology and trials of deep brain stimulation in that region for gait disturbances in Parkinson's disease. © 2010 Movement Disorder Society [source] Signaling by Neuronal Tyrosine Kinase Receptors: Relevance for Development and RegenerationTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 12 2009Barbara Hausott Abstract Receptor tyrosine kinase activation by binding of neurotrophic factors determines neuronal morphology and identity, migration of neurons to appropriate destinations, and integration into functional neural circuits as well as synapse formation with appropriate targets at the right time and at the right place. This review summarizes the most important aspects of intraneuronal signaling mechanisms and induced gene expression changes that underlie morphological and neurochemical consequences of receptor tyrosine kinase activation in central and peripheral neurons. Anat Rec, 292:1976,1985, 2009. © 2009 Wiley-Liss, Inc. [source] Australia's National Action Plan for Salinity and Water Quality: a retrospective assessment,AUSTRALIAN JOURNAL OF AGRICULTURAL & RESOURCE ECONOMICS, Issue 4 2010David J. Pannell Perceptions of a salinity ,crisis' in Australia around 2000 resulted in the establishment of a major national program that aimed to prevent, stabilize, and reverse trends in salinity. The National Action Plan for Salinity and Water Quality allocated A$1.4 billion of public funds to 1700 projects over 7 years. Here, we assess the performance of the program in relation to 12 features that we propose as being essential for programs that aim to address complex environmental problems. The features include use of technical information to guide investment prioritization, use of socio-economic information, effective integration of information for prioritization, selection of appropriate targets, choice of appropriate policy mechanisms, and provision of incentives and support to environmental managers to pursue environmental outcomes cost effectively. Our assessment reinforces findings from a number of public reviews that found serious weaknesses in the program. Overall, with a few exceptions, projects under the National Action Plan generated few worthwhile salinity mitigation benefits and will have little enduring benefit. This was readily foreseeable given attention to the scientific and economic knowledge of salinity available at the time the program was developed. [source] How to Achieve Confidence in Drug Discovery and Development: Managing Risk (from a Reductionist to a Holistic Approach)CHEMMEDCHEM, Issue 6 2009Annette Bakker Dr. Abstract Confidence in mechanism: Creating a more holistic understanding of disease pathophysiology and an early confidence in the mechanism under investigation could help facilitate the selection of not only the most appropriate targets but also the best mechanisms for disease intervention and how to select and optimise the best compounds. Drug target and candidate selection are two of the key decision points within the drug discovery process for which all companies use certain selection criteria to make decisions on which targets to accept into their discovery pipelines and which compounds will pass into development. These steps not only help define the overall productivity of every company but they are also decisions taken without full predictive knowledge of the risks that lie ahead or how best to manage them. In particular, the process of selecting new targets does not normally involve full evaluation of the risk(s) in the mechanism under investigation (the modulation of the target), which may result in an inability to fully connect in,vitro and animal model results to the disease (clinical) setting. The resulting poor progression statistics of many compounds in the clinic is at least partially the result of a lack of understanding of disease pathophysiology. Notably, the lack of efficacy is still a major reason for failure in the clinic.1 Creating a more holistic understanding of disease pathophysiology and an early confidence in the mechanism under investigation could help facilitate the selection of not only the most appropriate targets but also the best mechanisms for disease intervention and how to select and optimise the best compounds. [source] | ||||||||||||||||||||||||||||