Metformin treatment of diverse Caenorhabditis species reveals the importance of genetic background in longevity and healthspan extension outcomes

Metformin, the most commonly prescribed anti‐diabetes medication, has multiple reported health benefits, including lowering the risks of cardiovascular disease and cancer, improving cognitive function with age, extending survival in diabetic patients, and, in several animal models, promoting youthful physiology and lifespan. Due to its longevity and health effects, metformin is now the focus of the first proposed clinical trial of an anti‐aging drug—the Targeting Aging with Metformin (TAME) program. Genetic variation will likely influence outcomes when studying metformin health effects in human populations. To test for metformin impact in diverse genetic backgrounds, we measured lifespan and healthspan effects of metformin treatment in three Caenorhabditis species representing genetic variability greater than that between mice and humans. We show that metformin increases median survival in three C. elegans strains, but not in C. briggsae and C. tropicalis strains. In C. briggsae, metformin either has no impact on survival or decreases lifespan. In C. tropicalis, metformin decreases median survival in a dose‐dependent manner. We show that metformin prolongs the period of youthful vigor in all C. elegans strains and in two C. briggsae strains, but that metformin has a negative impact on the locomotion of C. tropicalis strains. Our data demonstrate that metformin can be a robust promoter of healthy aging across different genetic backgrounds, but that genetic variation can determine whether metformin has positive, neutral, or negative lifespan/healthspan impact. These results underscore the importance of tailoring treatment to individuals when testing for metformin health benefits in diverse human populations.     

Modelling Beauveria bassiana horizontal transmission

1 We modelled horizontal transmission of Beauveria bassiana in Colorado potato beetle (CPB) between larval cadavers and soil inhabiting prepupae. 2 The rate of disease transmission, based on the probability of a prepupa contacting sporulating cadavers on the soil surface, is a non‐linear function of cadaver density and also dependent upon temperature. 3 The spatial pattern of cadavers is needed to estimate prepupal contacts with cadavers. Observational field studies determined Johnson distributions to model the spatial pattern of cadavers and prepupae in the field. The model also implicitly incorporates within‐field larval spatial pattern into estimates of field‐level horizontal transmission. 4 Potential for horizontal transmission is higher in simulations using weather data from the warmer year of 1995, than in simulations of the cooler growing season of 1993. 5 Simulations of CPB populations under northern Maine climatic conditions recorded in 1993 and 1995 suggest that horizontal transmission can range from 3 to 24% depending upon the timing of primary infection of larvae in the field. 6 Two simulated sequential applications of B. bassiana targeted at peak first instars resulted in maximum horizontal infection in both years. 7 Sensitivity analysis suggests that horizontal transmission is most sensitive to changes in the proportion of cadavers that sporulate and least sensitive to changes in the time between larval death and the onset of cadaver sporulation. 8 Field validation of the model indicates good prediction of one measure of horizontal infection, the proportion of prepupae which eventually sporulated after being released in controlled field experiments.     

A test of pollinator specificity and morphological convergence between nectarivorous birds and rainforest tree flowers in New Guinea

Interactions between flowering trees in a representative sample of vegetation, and the birds that fed at their flowers, were studied for 2 years in lowland tropical hill forest in New Guinea. All 2,200 trees in a 3-ha plot were tagged, identified, mapped, and monitored monthly. Approximately 60% of all individual trees flowered during the study; all species that these flowering individuals belonged to were evaluated for bird visitation. Approximately 13% of the 164 resident species of New Guinea avifauna at the study site, especially honeyeaters and parrots, visited flowers. In the forest inventory plot, approximately 15–22% of all 86 tree species that flowered during the study were visited by birds; most of these tree species were canopy species. Results showed that there was no statistically significant correlation between bird species grouped by bill morphology and flower species grouped as morphotypes and ranked by nectar accessibility, although strong but unexpected bird/plant associations were evident. These associations may be related to variables such as body mass or perch size. These results are discussed in comparison with results from the Neotropics and Australia, and in terms of morphological convergence and pollinator specificity in pollination systems.     

Applications and Enrolments at the Western Medical Schools: A Study of Medical Matriculants for 1964

All applicants and those who subsequently enrolled for the 1964-65 session in the Western medical schools were studied with the hope that it would encourage a national registration of applicants. Seven hundred and sixty-four applicants completed 865 applications for 288 places in four schools. Although the principal factor in selecting medical students in all Western schools is pre-medical performance, 49 “good-quality” (academically of good standing and under 30 years of age) resident applicants were not accepted in their own provincial school, and 49 places were filled with “poor-quality” students.The loss of good applicants to the Western medical schools and the 20% overlap of each school''s applicant pool with that of other schools suggests that objective standards of quality must be developed, and that a regular annual national assessment of applicants should be conducted by the Association of Canadian Medical Colleges.     

Manganese-Resistant Mutants of Escherichia coli: Physiological and Genetic Studies

Manganese is growth inhibitory for Escherichia coli. The manganese concentration required for inhibition is dependent upon the magnesium concentration of the medium. Mutants have been isolated which are partially resistant to manganese inhibition in both liquid and solid media. From conjugation experiments, the genetic locus for manganese-resistance, mng, appears to be between 34 and 37 min on the E. coli genetic map. Experiments with radioactive (28)Mg lead to the tentative conclusion that the mng mutants are altered in the inhibition constant for manganese as a competitive inhibitor for the mangnesium accumulation system. Once high manganese enters the cells, it displaces internal magnesium and leads to a net cellular loss and hence growth inhibition. The mng mutants are somewhat less subject to manganese-induced magnesium loss under comparable conditions than are manganese-sensitive wild-type cells.     

Studies on the Pathway of Incorporation of 2-Aminopurine into the Deoxyribonucleic Acid of Escherichia coli

A pathway for the incorporation of 2-aminopurine into deoxyribonucleic acid (DNA) was studied in cell-free extracts of Escherichia coli. It was demonstrated that the free base can be converted to the deoxynucleoside, and that the deoxynucleotide can be phosphorylated to the di- and triphosphates and then incorporated into the DNA. From a consideration of the individual reactions in crude extracts, it is likely that the rate-limiting step in this pathway is the formation of the deoxynucleotide. Of especial interest is the observation that 2-aminopurine may be viewed as an analogue of either guanine or adenine, depending on which enzymatic step is being considered. On the one hand, it resembles guanine in that it is specifically converted from the mono- to the diphosphate by guanylate kinase and not by adenylate kinase. On the other hand, it replaces adenine rather than guanine in the DNA synthesized with purified DNA polymerases. E. coli DNA polymerase utilizes aminopurine deoxynucleoside triphosphate as a substrate for DNA synthesis much better than does purified phage T5-induced DNA polymerase and is also much less inhibited by this analogue than the T5 enzyme. These experiments in vitro correlate with known differential effects of 2-aminopurine on E. coli and phage in vivo.     

Movement of Sodium Across the Mucosal Surface of the Isolated Toad Bladder and its Modification by Vasopressin

Studies have been made on the isolated urinary bladder of the toad, Bufo marinus, in an attempt to evaluate gradients of chemical activity across the mucosal surfaces of the epithelial cells which would serve to maintain a net movement of sodium from the mucosal medium into the cells. The likelihood of such chemical gradients has been established by the demonstration of lower contents of sodium within the tissue, expressed as microequivalents per gram of tissue water, than of concentrations of sodium in the mucosal medium at all levels of the latter examined. The transepithelial transport of sodium and the sodium content of the tissue were found to increase rapidly with rise in concentration of sodium in the mucosal medium up to values of 30 to 60 meq per liter. Further increase in concentration of the medium above this value failed to induce further stimulation of sodium transport or increase in the sodium content of the tissue. Vasopressin increased the rate of transport of sodium at every concentration of sodium in the mucosal medium without altering this relationship. Although entry of sodium across the mucosal surface of the epithelial cells may be passive it is not by free diffusion but involves some considerable interaction with the mucosal surface of the bladder and constitutes the major determinant of the rate of transepithelial transport of sodium. Vasopressin acts to enhance this initial step in the transport of sodium.     

Comparison of Several Selective Media for Isolation and Differentiation of Coagulase-Positive Strains of Staphylococcus aureus

Six coagulase-positive strains of Staphylococcus aureus which had been cultivated in Brain Heart Infusion broth, milk, and brine were plated on seven isolation media. A significant difference in the growth patterns of the individual strains was found as well as a significant effect resulting from the previous cultivation history before plating. Brine and, to a lesser extent, milk were found to reduce maximal cell concentrations attained, but strains grown in brine and milk showed greater ability to withstand the selective action of the isolation media. Fibrinogen applied to the surface of five of the media allowed the formation of characteristic halos by coagulase-positive strains of S. aureus. Only half of the strains studied produced a zone of precipitation on SM110-Egg Yolk agar. The isolation medium containing cycloheximide and a high level of polymxin B was most inhibitory to the organisms.