Resistance of M. leprae to Quinolones: A Question of Relativity?

Multidrug resistant leprosy, defined as resistance to rifampin, dapsone and fluoroquinolones (FQ), has been described in Mycobacterium leprae. However, the in vivo impact of fluoroquinolone resistance, mainly mediated by mutations in DNA gyrase (GyrA₂GyrB₂), has not been precisely assessed. Our objective was to measure the impact of a DNA gyrase mutation whose implication in fluoroquinolone resistance has been previously demonstrated through biochemical studies, on the in vivo activity of 3 fluoroquinolones: ofloxacin, moxifloxacin and garenoxacin.

Methodology/Principal Findings

We used the proportional bactericidal method. 210 four-week-old immunodeficient female Nude mice (NMRI-Foxn1^nu/Foxn1^nu) were inoculated in the left hind footpad with 0.03 ml of bacterial suspension containing 5×10³, 5×10², 5×10¹, and 5×10⁰ M. leprae AFB organisms of strain Hoshizuka-4 which is a multidrug resistant strain harboring a GyrA A91V substitution. An additional subgroup of 10 mice was inoculated with 5×10⁻¹ bacilli in the untreated control group. The day after inoculation, subgroups of mice were treated with a single dose of ofloxacin, moxifloxacin, garenoxacin or clarithromycin at 150 mg/kg dosing. 12 months later mice were sacrificed and M. leprae bacilli were numbered in the footpad. The results from the untreated control group indicated that the infective inoculum contained 23% of viable M. leprae. The results from the moxifloxacin and garenoxacin groups indicated that a single dose of these drugs reduced the percentage of viable M. leprae by 90%, similarly to the reduction observed after a single dose of the positive control drug clarithromycin. Conversely, ofloxacin was less active than clarithromycin.

Conclusion/Significance

DNA gyrase mutation is not always synonymous of lack of in vivo fluoroquinolone activity in M. leprae. As for M. tuberculosis, in vivo studies allow to measure residual antibiotic activity in case of target mutations in M. leprae.     

Did the loss of phytoplanktivorous fish contribute to algal blooms in the Mwanza Gulf of Lake Victoria?

Possible causes of the increased algal blooms in Lake Victoria in the 1980s have been disputed by several authors; some suggested a top-down effect by the introduced Nile perch, whereas others suggested a bottom-up effect due to eutrophication. In this article the potential impact is established of grazing by fish on phytoplankton densities, before the Nile perch upsurge and the concomitant algal blooms in the Mwanza Gulf. The biomass and trophic composition of fish in the sublittoral area of the Mwanza Gulf were calculated based on catch data from bottom trawls, and from gill nets covering the whole water column. Estimates of phytoplankton production in the same area were made from Secchi values and chlorophyll concentrations. The total phytoplankton intake by fish was estimated at 230 mg DW m⁻² day⁻¹. The daily gross production ranged from 6,200 to 7,100 mg DW m⁻² day⁻¹ and the net production from 1,900 to 2,200 mg DW m⁻² day⁻¹. Thus, losses of phytoplankton through grazing by fish were about 3–4% of daily gross and 10–12% of daily net phytoplankton production. As a consequence it is unlikely that the phytoplankton blooms in the second half of the 1980s were due to a top-down effect caused by a strong decline in phytoplankton grazing by fish.     

Did alien ants initiate a population explosion of a coccoid plant pest on an islet in the Coral Sea?

The composition of the ant fauna of a Coral Sea islet, North East Herald Cay, is reported for several years from 1995 to 2007. A major change in composition was first noted in 2007 but probably occurred earlier. Tetramorium lanuginosum, present in 1997 and in previous years, was not found in 2007. Instead, Tetramorium bicarinatum, recorded for the first time in 2006, was abundant in 2007. This change, together with drier conditions, may have initiated a population explosion of a pest coccoid that caused serious damage to the tree, Pisonia grandis. Tetramorium bicarinatum also reduced the abundance of surface-active arthropods compared to their abundance when it was absent. Ants and other invertebrates on three other islets in the Coral Sea are also documented for 2007 and support the dominance effects of T. bicarinatums.     

Did Vaccination Slow the Spread of Bluetongue in France?

Vaccination is one of the most efficient ways to control the spread of infectious diseases. Simulations are now widely used to assess how vaccination can limit disease spread as well as mitigate morbidity or mortality in susceptible populations. However, field studies investigating how much vaccines decrease the velocity of epizootic wave-fronts during outbreaks are rare. This study aimed at investigating the effect of vaccination on the propagation of bluetongue, a vector-borne disease of ruminants. We used data from the 2008 bluetongue virus serotype 1 (BTV-1) epizootic of southwest France. As the virus was newly introduced in this area, natural immunity of livestock was absent. This allowed determination of the role of vaccination in changing the velocity of bluetongue spread while accounting for environmental factors that possibly influenced it. The average estimated velocity across the country despite restriction on animal movements was 5.4 km/day, which is very similar to the velocity of spread of the bluetongue virus serotype 8 epizootic in France also estimated in a context of restrictions on animal movements. Vaccination significantly reduced the propagation velocity of BTV-1. In comparison to municipalities with no vaccine coverage, the velocity of BTV-1 spread decreased by 1.7 km/day in municipalities with immunized animals. For the first time, the effect of vaccination has been quantified using data from a real epizootic whilst accounting for environmental factors known to modify the velocity of bluetongue spread. Our findings emphasize the importance of vaccination in limiting disease spread across natural landscape. Finally, environmental factors, specifically those related to vector abundance and activity, were found to be good predictors of the velocity of BTV-1 spread, indicating that these variables need to be adequately accounted for when evaluating the role of vaccination on bluetongue spread.     

Did postglacial sea-level changes initiate the evolutionary divergence of a Tasmanian endemic raptor from its mainland relative?

Populations on continental islands are often distinguishable from mainland conspecifics with respect to body size, appearance, behaviour or life history, and this is often congruent with genetic patterns. It is commonly assumed that such differences developed following the complete isolation of populations by sea-level rise following the Last Glacial Maximum (LGM). However, population divergence may predate the LGM, or marine dispersal and colonization of islands may have occurred more recently; in both cases, populations may have also diverged despite ongoing gene flow. Here, we test these alternative hypotheses for the divergence between wedge-tailed eagles from mainland Australia (Aquila audax audax) and the threatened Tasmanian subspecies (Aquila audax fleayi), based on variation at 20 microsatellite loci and mtDNA. Coalescent analyses indicate that population divergence appreciably postdates the severance of terrestrial habitat continuity and occurred without any subsequent gene flow. We infer a recent colonization of Tasmania by marine dispersal and cannot discount founder effects as the cause of differences in body size and life history. We call into question the general assumption of post-LGM marine transgression as the initiator of divergence of terrestrial lineages on continental islands and adjacent mainland, and highlight the range of alternative scenarios that should be considered.     

Can the heart initiate some forms of hypertension?

An active role for the heart in the initiation of hypertension can be postulated in two different sets of conditions. 1) Activation of pressor reflexes from the ventricles, coronary arteries, or aorta has been shown to produce substantial rises of arterial pressure; experience with postcoronary bypass hypertension suggests that these reflexes could be responsible for some types of paroxysmal hypertension. 2) Increased cardiac action caused by either neural or humoral factors can initiate a rise in cardiac output and blood pressure; sustained hypertension could be produced experimentally in conscious dogs by electrical stimulation of the stellate ganglion or by continuous infusion of dobutamine in the left coronary artery. Evidence suggesting that this could occur in humans was derived from a study of the relationship of cardiac output to cardiopulmonary volume in essential hypertension.     

Role of de Vries in the rediscovery of Mendel's paper. II. Did de Vries really understand Mendel's paper?

In this paper, we discuss briefly three of the several lines of evidence that we believe demonstrate de Vries's lack of understanding of Mendel's paper. In our view, at least part of de Vries's failure of understanding derives from the fact that he appears to have viewed Mendel's paper as being mainly about the inheritance of characters that was his own interest. Therefore, he looked at it to see whether Mendel had found any laws of inheritance. Mendel had done his research for another purpose, to find the laws describing the formation of hybrids and the development of their offspring. Thus, de Vries started his examination of Mendel's paper with a very fundamental misunderstanding of what it was about.     

Did Cyclic Metaphosphates Have a Role in the Origin of Life?

How life began still eludes science life, the initial progenote in the context presented herein, being a chemical aggregate of primordial inorganic and organic molecules capable of self-replication and evolution into ever increasingly complex forms and functions.

Presented is a hypothesis that a mineral scaffold generated by geological processes and containing polymerized phosphate units was present in primordial seas that provided the initiating factor responsible for the sequestration and organization of primordial life’s constituents. Unlike previous hypotheses proposing phosphates as the essential initiating factor, the key phosphate described here is not a polynucleotide or just any condensed phosphate but a large (in the range of at least 1 kilo-phosphate subunits), water soluble, cyclic metaphosphate, which is a closed loop chain of polymerized inorganic phosphate residues containing only phosphate middle groups. The chain forms an intrinsic 4-phosphate helix analogous to its structure in Na Kurrol’s salt, and as with DNA, very large metaphosphates may fold into hairpin structures. Using a Holliday-junction-like scrambling mechanism, also analogous to DNA, rings may be manipulated (increased, decreased, exchanged) easily with little to no need for additional energy, the reaction being essentially an isomerization.

A literature review is presented describing findings that support the above hypothesis. Reviewed is condensed phosphate inorganic chemistry including its geological origins, biological occurrence, enzymes and their genetics through eukaryotes, polyphosphate functions, circular polynucleotides and the role of the Holliday junction, previous biogenesis hypotheses, and an Eoarchean Era timeline.

     

II. Selective accumulation of MPP+ in the substantia nigra: A key to neurotoxicity?

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is rapidly metabolized to a 1-methyl-4-phenylpyridinium species (MPP+) in the squirrel monkey. After administration of toxic doses of MPTP, the concentration of MPP+ in the substantia nigra appears to increase during the first 72 hours, reaching the highest concentration of any central nervous system (CNS) tissue studied. In contrast, the concentration of this compound in other brain areas suggested time dependent elimination during the same period. Pretreatment of animals with the monoamine oxidase (MAO) inhibitor pargyline blocks both the neurotoxic action and the biotransformation of MPTP. In animals given pargyline and MPTP, initial MPTP levels are much higher in all brain regions than in those not receiving pargyline, but by 12 hours, MPTP levels had fallen rapidly in all regions except the substantia nigra and the eye. It may be that the selective toxicity of MPTP is related in some way to the accumulation of its oxidized metabolite in the substantia nigra.     

Characterization of an HLA-DR β pseudogene in the DRw52 supertypic group

The nature of the DR II pseudogene in a haplo-type of the DRw52 supertypic group was investigated by nucleotide sequence analysis. It revealed several deleterious mutations in the signal sequence and second domain regions in addition to the complete absence of the first domain and adjacent sequences. No expression of DR II pseudogene mRNA can be detected. The same DR II pseudogene is probably present in other members of the DRw52 supertypic group. The pattern of mutations in this DR II pseudogene is different from that observed in the DR pseudogene of the DRw53 supertypic group, indicating a distinct evolutionary pathway for these two groups of DR haplotypes.     

Did the evolution of the phytoplankton fuel the diversification of the marine biosphere?

We discuss the possible links between the fossil record of marine biodiversity, nutrient availability and primary productivity. The parallelism of the fossil records of marine phytoplankton and faunal biodiversity implicates the quantity (primary productivity) and quality (stoichiometry) of phytoplankton as being critical to the diversification of the marine biosphere through the Phanerozoic. The relatively subdued marine biodiversity of the Palaeozoic corresponds to a time of relatively low macronutrient availability and poor food quality of the phytoplankton as opposed to the diversification of the Modern Fauna through the Mesozoic–Cenozoic. Increasing nutrient runoff to the oceans through the Phanerozoic resulted from orogeny, the emplacement of Large Igneous Provinces (LIPs), the evolution of deep-rooting forests and the appearance of more easily decomposable terrestrial organic matter that enhanced weathering. Positive feedback by bioturbation of an expanding benthos played a critical role in evolving biogeochemical cycles by linking the oxidation of dead organic matter and the recycling of nutrients back to the water column where they could be re-utilized. We assess our conclusions against a recently published biogeochemical model for geological time-scales. Major peaks of marine diversity often occur near rising or peak fluxes of silica, phosphorus and dissolved reactive oceanic phosphorus; either major or minor ⁸⁷Sr/⁸⁶Sr peaks; and frequently in the vicinity of major (Circum-Atlantic Magmatic Province) and minor volcanic events, some of which are associated with Oceanic Anoxic Events. These processes appear to be scale-dependent in that they lie on a continuum between biodiversification on macroevolutionary scales of geological time and mass extinction.     

Cytokinin-enhanced accumulation of indole alkaloids in Catharanthus roseus cell cultures — The factors affecting the cytokinin response

Summary Cytokinins were found to stimulate the alkaloid synthesis induced by removing auxin from the medium of a cell line of Catharanthus roseus. Diluting the mineral salts of the culture medium decreased the alkaloid production but increased the sensitivity of the cells. Addition of high levels of Ca²⁺, Mg²⁺ or Sr²⁺ to B5 media in which the mineral salts were diluted to 5–40%, increased the alkaloid production. The latter effect is related only partially to enhanced osmotic potential.Abbreviations BA 6-benzylaminopurine - CK cytokinin - 2,4D 2,4-dichlorophenoxyacetic acid - dw dry weight - Kin 6-furfurylaminopurine - TLC thin layer chromatography - SE standard error - Z trans-zeatin     

Did births decline in the United States after the enactment of no-fault divorce law?

Previous research has demonstrated that U.S. no-fault divorce laws implemented between 1953 and 1987 resulted in more divorces in some states than would have occurred otherwise. In other states, divorce patterns appeared to follow prevailing trends even after implementation of no-fault divorce legislation. A more distal question is whether implementation of no-fault divorce laws had an effect on birth rates. We analyzed state-level birth data from all 50 states to assess the birth response to the enactment of no-fault divorce law in each state. Results suggested that birth rates decreased significantly two to four years following the enactment of no-fault divorce law for the group of 34 states whose divorce rates responded to no-fault divorce legislation. As predicted, among the 16 states whose divorce rates did not respond to no-fault divorce legislation, the enactment of no-fault divorce law had a small and nonsignificant positive influence on birth rates. Generally, the group of 34 states had lower post no-fault birth rates than the group of 16 states.     

M?ssbauer effect in rubredoxin. Determination of the hyperfine field of the iron in a simple iron–sulphur protein

1. Rubredoxin isolated from the green photosynthetic bacterium Chloropseudomonas ethylica was similar in composition to those from anaerobic fermentative bacteria. Amino acid analysis indicated a minimum molecular weight of 6352 with one iron atom per molecule. 2. The circular-dichroism and electron-paramagnetic-resonance spectra of Ch. ethylica rubredoxin showed many similarities to those of Clostridium pasteurianum, but suggested that there may be subtle differences in the protein conformation about the iron atom. 3. Mössbauer-effect measurements on rubredoxin from Cl. pasteurianum and Ch. ethylica showed that in the oxidized state the iron (high-spin Fe³⁺) has a hyperfine field of 370±3kG, whereas in the reduced state (high-spin Fe²⁺) the hyperfine field tensor is anisotropic with a component perpendicular to the symmetry axis of the ion of about −200kG. For the reduced protein the sign of the electric-field gradient is negative, i.e. the ground state of the Fe²⁺ is a [unk] orbital. There is a large non-cubic ligand-field splitting (Δ/k=900°K), and a small spin-orbit splitting (D~+4.4cm⁻¹) of the Fe²⁺ levels. 4. The contributions of core polarization to the hyperfine field in the Fe³⁺ and Fe²⁺ ions are estimated to be −370 and −300kG respectively. 5. The significance of these results in interpretation of the Mössbauer spectra of other iron–sulphur proteins is discussed.     

Did medicated salt hasten the spread of chloroquine resistance in Plasmodium falciparum?

With acknowledged difficulties in achieving satisfactory compliance rates for the large-scale delivery of many antiporositic drugs, the use of medicated salt has often been seen as a useful way to improve the level o f treatment in target populations. Iodinated salt is said to have contributed to a decline in endemic goitre, and salt medicated with chloroquine and/or other antimalorials, or with diethylcarbomazine, has been widely used in public health programmes against malaria and filariosis respectively. In this article, however, David Payne suggests that chloroquinized salt programmes may have been a major factor in promoting chloroquine resistance in Plasmodium falciparum.     

Did the first insects live in water or in air?

We evaluate the arguments and evidence for a terrestrial vs an aquatic origin for the Insecta. The evidence falls into three categories: (1) evidence that does not support one view more than the other; (2) speculative evidence, which should carry little weight; and (3) evidence that does support one view more than the other. Category 1 includes evidence from locomotory and osmoregulatory systems; plausible functions have been proposed for 'protowings' in both aquatic and terrestrial environments, while locomotory and osmoregulatory mechanisms of insects shed little light on their origins. Fossils, phylogenetic speculation, gill structure and life histories fall into category 2, in which, although speculative, the evidence favours a terrestrial origin. The earliest fossil hexapods were apparently terrestrial and unequivocally aquatic hexapods do not appear until 60–70 million years later, while sister-group relationships point to a terrestrial life style from at least the Hexapoda-Myriapoda stem group. The great variation in gill structure, even within orders, suggests convergence, and the more or less completely aquatic life histories are better interpreted as steps towards independence from land, rather than signs of an aquatic origin. Category 3 includes evidence from the tracheal system. In order to have evolved in water, a tracheal system must have first invaginated, then connected with the body wall for gas exchange with the water, and thirdly connected with the internal organs. It is difficult to envisage functions for the first two stages; on the other hand, the system could have readily evolved on land by invagination of respiratory surfaces, and then have been modified to effect gas exchange in water via gills.