Variations in frequencies of drug resistance in Plasmodium falciparum

Continual exposure of malarial parasite populations to different drugs may have selected not only for resistance to individual drugs but also for genetic traits that favor initiation of resistance to novel unrelated antimalarials. To test this hypothesis, different Plasmodium falciparum clones having varying numbers of preexisting resistance mechanisms were treated with two new antimalarial agents: 5-fluoroorotate and atovaquone. All parasite populations were equally susceptible in small numbers. However, when large populations of these clones were challenged with either of the two compounds, significant variations in frequencies of resistance became apparent. On one extreme, clone D6 from West Africa, which was sensitive to all traditional antimalarial agents, failed to develop resistance under simple nonmutagenic conditions in vitro. In sharp contrast, the Indochina clone W2, which was known to be resistant to all traditional antimalarial drugs, independently acquired resistance to both new compounds as much as a 1,000 times more frequently than D6. Additional clones that were resistant to some (but not all) traditional antimalarial agents acquired resistance to atovaquone at high frequency, but not to 5-fluoroorotate. These findings were unexpected and surprising based on current views of the evolution of drug resistance in P. falciparum populations. Such new phenotypes, named accelerated resistance to multiple drugs (ARMD), raise important questions about the genetic and biochemical mechanisms related to the initiation of drug resistance in malarial parasites. Some potential mechanisms underlying ARMD phenotypes have public health implications that are ominous.

Copy Number Variations in DISC1 and DISC1-Interacting Partners in Major Mental Illness

Acknowledgements We would like to thank all of the patients, relatives and control individuals who participated in the study. We are indebted to the late Prof. Walter Muir, Chair of Developmental Psychiatry and Honorary Consultant in Learning Disability Psychiatry, University of Edinburgh, who initiated these studies and whose work was dedicated to the welfare of the patients who generously participated. We are also grateful to Mrs. Pat Malloy for her assistance with DNA collection and MAQ assays screening of the Scottish samples. The Scottish sample collection was supported by a grant from the Chief Scientist Office (CSO), part of the Scottish Government Health and Social Care Directorates. This research was funded by grants from the CSO to B.S.P. (grant CZB/4/610), The Academy of Medical Sciences/Wellcome Trust to M.J. (grant R41455) and The RS Macdonald Charitable Trust (grant D21419 together with J.H.), the Swedish Research Council (grants 2003-5158 and 2006-4472), the Medical Faculty, Umeå University, and the County Councils of Västerbotten and Norrbotten, Sweden, as well as by grants from the Fund for Scientific Research Flanders (FWO-F), the Industrial Research Fund (IWT) and the Special Research Fund of the University of Antwerp, Belgium. M.J. is funded by a Wellcome Trust Clinical Research Fellowship for MB PhD graduates (R42811). We acknowledge the contribution of the personnel of the VIB Genetic Service Facility (http://www.vibgeneticservicefacility.be/) for the genetic analysis of the Swedish samples. Research nurses Gunnel Johansson, Lotta Kronberg, Tage Johansson and Lisbeth Bertilsson are thankfully acknowledged for their help and expertise. The Betula Study was funded by the Swedish Research Council (grants 345-2003-3883 and 315-2004-6977). We also acknowledge the contribution by the staff in the Betula project

Landscape influence on small-scale water temperature variations in a moorland catchment

Peer reviewed

Telomeres in the mouse have large inter-chromosomal variations in the number of T2AG3 repeats

The ultra-long telomeres that have been observed in mice are not in accordance with the concept that critical telomere shortening is related to aging and immortalization. Here, we have used quantitative fluorescence in situ hybridization to estimate (T2AG3)n lengths of individual telomeres in various mouse strains. Telomere lengths were very heterogeneous, but specific chromosomes of bone marrow cells and skin fibroblasts from individual mice had similar telomere lengths. We estimate that the shortest telomeres are around 10 kb in length, indicating that each mouse cell has a few telomeres with (T2AG3)n lengths within the range of human telomeres. These short telomeres may be critical in limiting the replicative potential of murine cells.

Variations in population health status: results from a United Kingdom national questionnaire survey

Objective: To measure the health of a representative sample of the population of the United Kingdom by using the EuroQoL EQ-5D questionnaire.

The μ opiate receptor as a candidate gene for pain: Polymorphisms, variations in expression, nociception, and opiate responses

There are differences between human individuals and between mouse strains in levels of μ opiate receptor (μOR) expression, responses to painful stimuli, and responses to opiate drugs. One of the best candidates for contributing to these differences is variation at the μOR gene locus. Support for this idea comes from analyses of the human and murine μOR genes. Assessments of individual differences in human μOR expression add further support. Studies with mice, including knockout-transgenic, quantitative trait locus, and strain-comparison studies, also strongly support the possibility that μOR gene alleles would be strong candidates for contributing to individual differences in human nociception and opiate drug responses. This paper reviews current analyses of the murine and human μOR genes, their important variants, and correlations between these variants and opiate influences on pain.

Pancreatic digestive enzyme secretion in the rabbit: rapid cyclic variations in enzyme composition.

The role and mechanism of nonparallel pancreatic secretion of digestive enzymes, in which enzyme proportions change in rapidly regulated fashion, remain controversial. Secretion was collected from male 2.2-kg New Zealand rabbits in 5-min intervals for 3 h under basal conditions or constant stimulation with cholecystokinin (CCK; 0.1 microgram per kg per h i.v.) or methacholine chloride (MCh; 40 micrograms per kg per h i.v.). Both CCK and MCh produced an 8-fold stimulation of protein output. Enzymes were separated by SDS/PAGE and quantitated by densitometry of Coomassie blue-stained gels. Under both basal conditions and constant MCh infusion, rapid neurosecretory-like 12-min cyclic changes occurred in the proportions of amylase, lipase I, chymotrypsinogen, and trypsinogen. During constant infusion their percentages changed as much as 10-fold, and their ratios cycled by as much as 30-fold. The mean percentage for the entire infusion period for lipase I declined > 25% with CCK or MCh, for amylase it rose approximately 30%, and for chymotrypsinogen and trypsinogen it doubled (for all, P < 0.05). CCK and MCh elicited subtly but significantly different mean enzyme percentages and enzyme ratios (P < 0.05) for amylase, chymotrypsinogen, and trypsinogen; these differences were also confirmed by regression and correlation analyses. The changes in enzyme percentages and ratios were explicitly consistent with secretagogue-caused shifts in the intrapancreatic enzyme secretory sources. Nonparallel secretion of digestive enzymes occurs routinely, even during constant stimulation, and is due to cyclic neurosecretory-like secretion from heterogeneous intrapancreatic sources.

Steric and mass-induced sea level variations in the Mediterranean Sea revisited

The total sea level variation (SLV) is the combination of steric and mass␣induced SLV, whose exact shares are key to understanding the oceanic response to climate system changes. Total SLV can be observed by radar altimetry satellites such as TOPEX/POSEIDON and Jason 1/2. The steric SLV can be computed through temperature and salinity profiles from in situ measurements or from ocean general circulation models (OGCM), which can assimilate the said observations. The mass-induced SLV can be estimated from its time-variable gravity (TVG) signals. We revisit this problem in the Mediterranean Sea estimating the observed, steric, and mass-induced SLV, for the latter we analyze the latest TVG data set from the GRACE (Gravity Recovery and Climate Experiment) satellite mission launched in 2002, which is 3.5 times longer than in previous studies, with the application of a two-stage anisotropic filter to reduce the noise in high-degree and -order spherical harmonic coefficients. We confirm that the intra-annual total SLV are only produced by water mass changes, a fact explained in the literature as a result of the wind field around the Gibraltar Strait. The steric SLV estimated from the residual of “altimetry minus GRACE” agrees in phase with that estimated from OGCMs and in situ measurements, although showing a higher amplitude. The net water fluxes through both the straits of Gibraltar and Sicily have also been estimated accordingly.

On the steric and mass-induced contributions to the annual sea level variations in the Mediterranean Sea

The sea level variation (SLVtotal) is the sum of two major contributions: steric and mass-induced. The steric SLVsteric is that resulting from the thermal and salinity changes in a given water column. It only involves volume change, hence has no gravitational effect. The mass-induced SLVmass, on the other hand, arises from adding or subtracting water mass to or from the water column and has direct gravitational signature. We examine the closure of the seasonal SLV budget and estimate the relative importance of the two contributions in the Mediterranean Sea as a function of time. We use ocean altimetry data (from TOPEX/Poseidon, Jason 1, ERS, and ENVISAT missions) to estimate SLVtotal, temperature, and salinity data (from the Estimating the Circulation and Climate of the Ocean ocean model) to estimate SLVsteric, and time variable gravity data (from Gravity Recovery and Climate Experiment (GRACE) Project, April 2002 to July 2004) to estimate SLVmass. We find that the annual cycle of SLVtotal in the Mediterranean is mainly driven by SLVsteric but moderately offset by SLVmass. The agreement between the seasonal SLVmass estimations from SLVtotal – SLVsteric and from GRACE is quite remarkable; the annual cycle reaches the maximum value in mid-February, almost half a cycle later than SLVtotal or SLVsteric, which peak by mid-October and mid-September, respectively. Thus, when sea level is rising (falling), the Mediterranean Sea is actually losing (gaining) mass. Furthermore, as SLVmass is balanced by vertical (precipitation minus evaporation, P–E) and horizontal (exchange of water with the Atlantic, Black Sea, and river runoff) mass fluxes, we compared it with the P–E determined from meteorological data to estimate the annual cycle of the horizontal flux.

Reply to comment by L. Fenoglio-Marc et al. on “On the steric and mass-induced contributions to the annual sea level variations in the Mediterranean Sea”

Reply to comment by L. Fenoglio-Marc et al. on “On the steric and mass-induced contributions to the annual sea level variations in the Mediterranean Sea”.

Short-term variations in radiolarian faunal dsitribution in the eastern equatorial Pacific

Two short time intervals centered at 2.3 and 4.7 Ma were studied to investigate short-term variations in surface-ocean processes as indicated by changes in the radiolarian microfossil population. These time intervals represent two different settings of late Neogene climate. The older interval represents a time when tropical circulation between the Pacific and Atlantic oceans was not blocked by the Isthmus of Panama, whereas the younger interval represents a time when Northern Hemisphere glaciation was present but did not display the dominance of the 100,000-yr cycle that characterizes the late Pleistocene. The younger time slice at 2.3 Ma was sampled at all Leg 138 sites except Site 844, where significant reworking was evident. All sites except 844, 853, and 854 were sampled for the older time slice. Samples were taken at 10- to 20-cm intervals at each site and spanned a GRAPE density maximum and minimum. Thus, it was possible to investigate whether the changes in carbonate content (as indicated by GRAPE density) were associated with changes in surface-ocean conditions (indicated by radiolarian assemblage variations). For both time slices, the radiolarian data indicate that intervals of decreased carbonate content are periods of cooler water conditions and possibly enhanced biogenic production. Times of increased carbonate content are associated with inferred warmer oceanographic conditions, as indicated by the dominance of tropical assemblages at 2.3 Ma and tropical and western Pacific assemblages during the time slice centered at 4.8 Ma. However, the spatial patterns of change during each time slice show a distinct difference in the mapped patterns of radiolarian assemblage dominance. The older time slice, representing a period before the closing of the Isthmus of Panama, shows more zonal patterns presumably associated with a more zonal character of equatorial circulation. After the closing of the isthmus, the shifts in faunal patterns between times of high and low carbonates are characterized by shifts in the dominance of the tropical and transitional assemblages, respectively, throughout the region.