Can landscape ecology untangle the complexity of antibiotic resistance?

Bacterial resistance to antibiotics continues to pose a serious threat to human and animal health. Given the considerable spatial and temporal heterogeneity in the distribution of resistance and the factors that affect its evolution, dissemination and persistence, we argue that antibiotic resistance must be viewed as an ecological problem. A fundamental difficulty in assessing the causal relationship between antibiotic use and resistance is the confounding influence of geography: the co-localization of resistant bacterial species with antibiotic use does not necessarily imply causation and could represent the presence of environmental conditions and factors that have independently contributed to the occurrence of resistance. Here, we show how landscape ecology, which links the biotic and abiotic factors of an ecosystem, might help to untangle the complexity of antibiotic resistance and improve the interpretation of ecological studies.     

Effect of NG-monomethyl-L-arginine on the β-adrenoceptor-mediated relaxation of rat mesenteric resistance arteries

β-Adrenoceptors are present on vascular smooth muscle and on endothelium. We investigated whether the endothelial β-adrenoceptors induce relaxation of rat mesentric resistance arteries by stimulation of endothelium-derived relaxing factor (EDRF) release. To this end, the relaxation was studied in the presence and absence of 100 μM N^G-monomethyl-L-arginine (L-NMMA), a specific inhibitor of the production of EDRF. The maximal relaxation with isoprenaline, expressed as a percentage of the precontraction, was 44.0 ± 4.0 % (n = 12) in the L-NMMA treated group and 58.0 ± 2.6 % (n = 13) in the untreated group, a statistically significant difference (P = 0.008). However, the precontraction with 40 mM K⁺ tended to be higher in the presence of L-NMMA. The pD₂-value for isoprenaline was not significantly changed by the L-NMMA treatment. We conclude that the isoprenaline-mediated relaxation of mesenteric resistance arteries in inhibited by L-NMMA, bu that this effect can at least in part be ascribed to an inhibition of baseline EDRF-release.     

The evolution of insecticide resistance: Have the insects won?

While insecticides have greatly improved human health and agricultural production worldwide, their utility has been limited by the evolution of resistance in many major pests, including some that became pests only as a result of insecticide use. Insecticide resistance is both an interesting example of the adaptability of insect pests, and, in the design of resistance management programmes, a useful application of evolutionary biology. Pest susceptibility is a valuable natural resource that has been squandered; at the same time, it is becoming increasingly expensive to develop new insecticides. Pest control tactics should therefore take account of the possibility of resistance evolution. One of the best ways to retard resistance evolution is to use insecticides only when control by natural enemies fails to limit economic damage. This review summarizes the recent literature on insecticide resistance as an example of adaptation, and demonstrates how population genetics and ecology can be used to manage the resistance problem.     

Virulence and resistance in malaria: who drives the outcome of the infection?

Theoretical and experimental studies have established the dynamic nature of virulence and that, like all traits, it has evolved. Understanding parasite evolution offers a conceptual framework for diverse fields and can contribute greatly to decision-making in disease control. Recently, Grech et al. investigated the effects of host genotype-by-parasite genotype interactions on the expression of virulence in an artificial rodent-malaria system. They found that both parasite and host effects explained most of the variance in the virulence, resistance and transmission potential. These findings are a major contribution to the emerging debate on the pros and cons of a coevolutionary approach of virulence evolution; they also hold great potential for more effective control strategies.     

Assessment of the importance of α-amylase inhibitor-2 in bruchid resistance of wild common bean

Both α-amylase inhibitor-2 (αAI-2) and arcelin have been implicated in resistance of wild common bean (Phaseolus vulgaris L.) to the Mexican bean weevil (Zabrotes subfasciatus Boheman). Near isogenic lines (NILs) for arcelin 1–5 were generated by backcrossing wild common bean accessions with a cultivated variety. Whereas seeds of a wild accession (G12953) containing both αAI-2 and arcelin 4 were completely resistant to Z. subfasciatus, those of the corresponding NIL were susceptible to infestation, suggesting that the principal determinant of resistance was lost during backcrossing. Three independent lines of transgenic azuki bean [Vigna angularis (Willd.) Ohwi and Ohashi] expressing αAI-2 accumulated high levels of this protein in seeds. The expression of αAI-2 in these lines conferred protection against the azuki bean weevil (Callosobruchus chinensis L.), likely through inhibition of larval digestive α-amylase. However, although the seed content of αAI-2 in these transgenic lines was similar to that in a wild accession of common bean (G12953), it did not confer a level of resistance to Z. subfasciatus similar to that of the wild accession. These results suggest that αAI-2 alone does not provide a high level of resistance to Z. subfasciatus. However, αAI-2 is an effective insecticidal protein with a spectrum of activity distinct from that of αAI-1, and it may prove beneficial in genetic engineering of insect resistance in legumes.     

Does acetylcholine change the electrical resistance of the basal membrane of secretory cells in eccrine sweat glands?

Summary The present experiment was intended to study whether or not acetylcholine decreases the electrical resistance of the basal membrane of secretory cells in stimulating eccrine secretion of fluid and electrolytes. An isolated segment of the secretory coil of the monkey palm eccrine sweat gland was dissected outin vitro and immobilized in the tip of a constriction pipette. Using a bridge-balanced single glass microelectrode, input impedance of the secretory cell was compared before and after local superfusion of acetylcholine in each cell. The mean input impedance was 27m, which did not significantly change after application of acetylcholine. Between 15 and 30 sec after cessation of acetylcholine superfusion, input impedance increased by 42% and then returned to normal within 60 sec. The current-induced voltage deflection due to intraluminally injected current pulse was measured across both the basal membrane (V _b ) and the epithelial wall (V _t ) as qualitative measures of the respective membrane resistances. Both V _b and V _t increased by about 10%, but their ratio remained unchanged after stimulation with acetylcholine. A Ca⁺⁺ ionophore, A23187, which is as potent a stimulant of eccrine sweat secretion as acetylcholinein vitro, also failed to change the above two parameters. It was concluded that the decrease in the electrical resistance of the basal membrane of the secretory cells could not be detected in the sweat gland after stimulation with acetylcholine or A23187. The possibility was discussed that the action of acetylcholine at the basal membrane is one of enhancing the activity of the nonconductive pathway rather than the conductive pathway in this exocrine gland.     

Three years of insecticide resistance monitoring in Anopheles gambiae in Burkina Faso: resistance on the rise?

ABSTRACT: Background and methods A longitudinal Anopheles gambiae s.l. insecticide-resistance monitoring programme was established in four sentinel sites in Burkina Faso. For three years, between 2008 and 2010, WHO diagnostic dose assays were used to measure the prevalence of resistance to all the major classes of insecticides at the beginning and end of the malaria transmission season. Species identification and genotyping for target site mutations was also performed and the sporozoite rate in adults determined. RESULTS: At the onset of the study, resistance to DDT and pyrethroids was already prevalent in An. gambiae s.l. from the south-west of the country but mosquitoes from the two sites in central Burkina Faso were largely susceptible. Within three years, DDT and permethrin resistance was established in all four sites. Carbamate and organophosphate resistance remains relatively rare and largely confined to the south-western areas although a small number of bendiocarb survivors were found in all sites by the final round of monitoring. The ace-1R target site resistance allele was present in all localities and its frequency exceeded 20% in 2010 in two of the sites. The frequency of the 1014 F kdr mutation increased throughout the three years and by 2010, the frequency of 1014 F in all sites combined was 0.02 in Anopheles arabiensis, 0.56 in An. gambiae M form and 0.96 in An. gambiae S form. This frequency did not differ significantly between the sites. The 1014 S kdr allele was only found in An. arabiensis but its frequency increased significantly throughout the study (P = 0.0003) and in 2010 the 1014 S allele frequency was 0.08 in An. arabiensis. Maximum sporozoite rates (12%) were observed in Soumousso in 2009 and the difference between sites is significant for each year. CONCLUSION: Pyrethroid and DDT resistance is now established in An. gambiae s.l. throughout Burkina Faso. Results from diagnostic dose assays are highly variable within and between rounds of testing, and hence it is important that resistance monitoring is carried out on more than one occasion before decisions on insecticide procurement for vector control are made. The presence of 1014 S in An. gambiae s.l., in addition to 1014 F, is not unexpected given the recent report of 1014 S in Benin but highlights the importance of monitoring for both mutations throughout the continent. Future research must now focus on the impact that this resistance is having on malaria control in Burkina Faso.     

Can periods of static loading be used to enhance the resistance of the spine to cumulative compression?

Results of in vitro studies conducted on isolated bone specimens have indicated a higher tolerance to static load than exists when exposed to cyclic loading, when controlled for creep rate. If this difference in load tolerance exists, it may be exploited to extend the life of vertebral bone exposed to repetitive compression, and potentially alter the development of spinal injury. However, little work has been conducted on functional spinal units to determine if bone displays this characteristic within an intact joint. Additionally, static loading may result in load redistribution within the intervertebral disc forcing more of the compressive load towards the periphery of the endplate away from the nucleus. In order to examine these potential mechanisms, 218 osteoligamentous porcine functional spinal units were assigned to one of 15 loading scenarios. This involved one of three normalized peak load magnitudes (50%, 70% and 90% of estimated compressive tolerance) and one of five normalized static load applications (0%, 50%, 100%, 200% and 1000% of the total dynamic work duration). Load magnitude significantly altered the resistance to cumulative compression with decreased peak magnitudes corresponding to both increased cumulative load tolerance and increased height loss. Static load periods did not alter the resistance of the spinal unit to cumulative compression or impact the number of cycles tolerated to failure. The insertion of static load periods impacted the total survival time to failure, but only for the 1000% static load group, an exposure unlikely to occur for most in vivo exposures. The insertion of static load periods decreased the amount of height loss during testing which may play a protective role by allowing load redistribution within the vertebral bone and intervertebral disc.     

What do we know about the mechanisms of aromatase inhibitor resistance?

Clinical trials have demonstrated the importance of aromatase inhibitor (AI) therapy in the effective treatment of hormone-dependent breast cancers. Yet, as with all prolonged drug therapy, resistance to aromatase inhibitors does develop. To date, the precise mechanism responsible for resistance to aromatase inhibitors is not completely understood. In this paper, several mechanisms of de novo/intrinsic resistance and acquired resistance to AIs are discussed. These mechanisms are hypothesized based on important findings from a number of laboratories.

To better understand this question, our lab has generated, in vitro, breast cancer cell lines that are resistant to aromatase inhibitors. Resistant cell lines were generated over a prolonged period of time using the MCF-7aro (aromatase overexpressed) breast cancer line. These cell lines are resistant to the aromatase inhibitors letrozole, anastrozole and exemestane and the anti-estrogen tamoxifen, for comparison. Two types of resistant cell lines have been generated, those that grow in the presence of testosterone (T) which is needed for cell growth, and resistant lines that are cultured in the presence of inhibitor only (no T). In addition to functional characterization of aromatase and ER in these resistant cell lines, microarray analysis has been employed in order to determine differential gene expression within the aromatase inhibitor resistant cell lines versus tamoxifen, in order to better understand the mechanism responsible for AI resistance on a genome-wide scale. We anticipate that our studies will generate important information on the mechanisms of AI resistance. Such information can be valuable for the development of treatment strategies against AI-resistant breast cancers.     

Is the molecular basis of metronidazole resistance in microaerophilic organisms understood?

Metronidazole is an antibiotic that has been effective against many microaerophilic microorganisms with importance in medicine and animal husbandry. The development of increasing resistance against current treatments by many of these organisms has created an urgent need to establish the molecular bases of resistance, knowledge which will help to develop novel diagnostic methods and identify new therapeutic targets. Significant progress has been made in understanding resistance to this antibiotic in the human pathogens Helicobacter pylori and, to a lesser extent, Campylobacter spp. However, insufficient knowledge of the physiology and genetics of these and other related bacteria has led to investigations based on hypotheses that themselves must be established more thoroughly. This review presents the status of our current knowledge of metronidazole resistance and outlines reasons to explain some of the conflicting evidence and controversy in the interpretation of results in this area.     

Hydraulic architecture of leaf blades: where is the main resistance?

The hydraulic architecture of Laurus nobilis L. and Juglans regia L. leaves was studied using three different approaches: (1) hydraulic measurements of both intact leaves and of leaves subjected to treatments aimed at removing the extra‐vascular resistance; (2) direct measurements of the vascular pressure with a pressure probe; and (3) modelling the hydraulic architecture of leaf venation system on the basis of measurements of vein densities and conductivities. The hydraulic resistance of leaves (R_leaf) either cut, boiled or frozen–thawed was reduced by about 60 and 85% with respect to control leaves for laurel and walnut, respectively. Direct pressure drop measurements suggested that 88% of the resistance resided outside the vascular system in walnut. Model simulations were in agreement with these results provided vein hydraulic conductance was 0.12–0.28 that of the conductance predicted by Poiseuille's law. The results suggest that R_leaf is dominated by substantial extra‐vascular resistances and therefore contrast with the conclusions of recent studies dealing with the hydraulic architecture of the leaf. The present study confirms the ‘classical’ view of the hydraulic architecture of leaves as composed by a low‐resistance component (the venation) and a high‐resistance component (the mesophyll).     

Insulin resistance in the liver: Deficiency or excess of insulin?

In insulin-resistant states (obesity, pre-diabetes, and type 2 diabetes), hepatic production of glucose and lipid synthesis are heightened in concert, implying that insulin deficiency and insulin excess coexists in this setting. The fact that insulin may be inadequate or excessive at any one point in differing organs and tissues has many biologic ramifications. In this context the concept of metabolic compartmentalization in the liver is offered herein as one perspective of this paradox. In particular, we focus on the hypothesis that insulin resistance accentuates differences in periportal and perivenous hepatocytes, namely periportal glucose production and perivenous lipid synthesis. Subsequently, excessive production of glucose and accumulation of lipids could be expected in the livers of patients with obesity and insulin resistance. Overall, in this review, we provide our integrative perspective regarding how excessive production of glucose in periportal hepatocytes and accumulation of lipids in perivenous hepatocytes interact in insulin resistant states.     

Unraveling the resistance of microbial biofilms: has proteomics been helpful?

Biofilms are surface-attached, matrix-encased, structured microbial communities which display phenotypic features that are dramatically different from those of their free-floating, or planktonic, counterparts. Biofilms seem to be the preferred mode of growth of microorganisms in nature, and at least 65% of all human infections are associated with biofilms. The most notable and clinically relevant property of biofilms is their greater resistance to antimicrobials compared with their planktonic counterparts. Although both bacterial and fungal biofilms display this phenotypic feature, the exact mechanisms underlying their increased drug resistance are yet to be determined. Advances in proteomics techniques during the past decade have facilitated in-depth analysis of the possible mechanisms underpinning increased drug resistance in biofilms. These studies have demonstrated the ability of proteomics techniques to unravel new targets for combating microbial biofilms. In this review, we discuss the putative drug resistance mechanisms of microbial biofilms that have been uncovered by proteomics and critically evaluate the possible contribution of the new knowledge to future development in the field. We also summarize strategic uses of novel proteomics technologies in studies related to drug resistance mechanisms of microbial biofilms.     

Bacteria–bacteria interactions within the microbiota of the ancestral metazoan Hydra contribute to fungal resistance

Epithelial surfaces of most animals are colonized by diverse microbial communities. Although it is generally agreed that commensal bacteria can serve beneficial functions, the processes involved are poorly understood. Here we report that in the basal metazoan Hydra, ectodermal epithelial cells are covered with a multilayered glycocalyx that provides a habitat for a distinctive microbial community. Removing this epithelial microbiota results in lethal infection by the filamentous fungus Fusarium sp. Restoring the complex microbiota in gnotobiotic polyps prevents pathogen infection. Although mono-associations with distinct members of the microbiota fail to provide full protection, additive and synergistic interactions of commensal bacteria are contributing to full fungal resistance. Our results highlight the importance of resident microbiota diversity as a protective factor against pathogen infections. Besides revealing insights into the in vivo function of commensal microbes in Hydra, our findings indicate that interactions among commensal bacteria are essential to inhibit pathogen infection.     

Increased Aβ production prompts the onset of glucose intolerance and insulin resistance

Type 2 diabetes (T2D) mellitus and Alzheimer's disease (AD) are two prevalent diseases with comparable pathophysiological features and genetic predisposition. Patients with AD are more susceptible to develop T2D. However, the molecular mechanism linking AD and T2D remains elusive. In this study, we have generated a new mouse model to test the hypothesis that AD would prompt the onset of T2D in mice. To test our hypothesis, we crossed Alzheimer APPswe/PS1dE9 (APP/PS1) transgenic mice with mice partially deficient in leptin signaling (db/+). Body weight, plasma glucose, and insulin levels were monitored. Phenotypic characterization of glucose metabolism was performed using glucose and insulin tolerance tests. β-Cell mass, islet volume, and islet number were analyzed by histomorphometry. APP/PS1 coexpression in mice with intact leptin receptor signaling did not show any metabolic perturbations in glucose metabolism or insulin sensitivity. In contrast, APP/PS1 coexpression in db/+ mice resulted in nonfasting hyperglycemia, hyperinsulinemia, and hypercholesterolemia without changes in body weight. Conversely, fasting blood glucose and cholesterol levels remained unchanged. Coinciding with altered glucose metabolism, APP/PS1 coexpression in db/+ mice resulted in glucose intolerance, insulin resistance, and impaired insulin signaling. In addition, histomorphometric analysis of pancreata revealed augmented β-cell mass. Taken together, these findings provide experimental evidence to support the notion that aberrant Aβ production might be a mechanistic link underlying the pathology of insulin resistance and T2D in AD.     

Biomechanism of impact resistance in the woodpecker’s head and its application

The woodpecker does not suffer head/eye impact injuries while drumming on a tree trunk with high acceleration(more than 1000×g) and high frequency.The mechanism that protects the woodpecker’s head has aroused the interest of ornithologists,biologists and scientists in the areas of mechanical engineering,material science and electronics engineering.This article reviews the literature on the biomechanisms and materials responsible for protecting the woodpecker from head impact injury and their applications in engineering and human protection.     

Does the strength of facilitation by nurse shrubs depend on grazing resistance of tree saplings?

Facilitation of tree regeneration by nurse shrubs that offer protection against large herbivores is an important driver of wood-pasture dynamics. Here we asked whether the response to facilitation by nurse shrubs depends on the grazing resistance of the protégé saplings. We experimentally tested the protective effects of the thorny Rosa rubiginosa on browsing frequency, survival, and biomass change of saplings of two species-groups, presumably differing in grazing resistance: the coniferous Abies alba and Picea abies and the deciduous Acer pseudoplatanus and Fagus sylvatica saplings. The saplings were planted under and outside (1.5 m) planted nurse shrubs, under zero, low and high grazing intensity. In total, 1920 young saplings were transplanted to 60 blocks and followed for 1 year.Although the number of saplings browsed did not differ between species-groups, the coniferous saplings showed lower resistance to cattle browsing (i.e. lower survival and growth rates) than the deciduous saplings. The less resistant coniferous saplings benefited significantly more from nurse shrubs than the more resistant deciduous species in terms of growth of the surviving saplings, but not in terms of overall survival. This was likely due to herbivory on the nurse shrubs causing incidental browsing on protégé saplings and differences in biomass off-take. At high grazing intensity facilitative effects of the nurse shrubs decreased, especially for the coniferous species.These results have important management implications for the endangered wood-pastures in Western Europe. For a sustainable management and conservation that allows tree recruitment, grazing intensity should remain low to best promote facilitation processes for all tree species, but in particular for the less resistant conifer saplings.