Little is known about the effects of intermittent preventive treatment of malaria in pregnancy (IPTp) on the health of sub-Saharan African infants. We have evaluated the safety of IPTp with mefloquine (MQ) compared to sulfadoxine-pyrimethamine (SP) for important infant health and developmental outcomes.
Methods and Findings
In the context of a multicenter randomized controlled trial evaluating the safety and efficacy of IPTp with MQ compared to SP in pregnancy carried out in four sub-Saharan countries (Mozambique, Benin, Gabon, and Tanzania), 4,247 newborns, 2,815 born to women who received MQ and 1,432 born to women who received SP for IPTp, were followed up until 12 mo of age. Anthropometric parameters and psychomotor development were assessed at 1, 9, and 12 mo of age, and the incidence of malaria, anemia, hospital admissions, outpatient visits, and mortality were determined until 12 mo of age. No significant differences were found in the proportion of infants with stunting, underweight, wasting, and severe acute malnutrition at 1, 9, and 12 mo of age between infants born to women who were on IPTp with MQ versus SP. Except for three items evaluated at 9 mo of age, no significant differences were observed in the psychomotor development milestones assessed. Incidence of malaria, anemia, hospital admissions, outpatient visits, and mortality were similar between the two groups. Information on the outcomes at 12 mo of age was unavailable in 26% of the infants, 761 (27%) from the MQ group and 377 (26%) from the SP group. Reasons for not completing the study were death (4% of total study population), study withdrawal (6%), migration (8%), and loss to follow-up (9%).
Conclusions
No significant differences were found between IPTp with MQ and SP administered in pregnancy on infant mortality, morbidity, and nutritional outcomes. The poorer performance on certain psychomotor development milestones at 9 mo of age in children born to women in the MQ group compared to those in the SP group may deserve further studies.
Proteasome-addicted neoplastic malignancies present a considerable refractory and relapsed phenotype with patients exhibiting drug resistance and high mortality rates. To counter this global problem, novel proteasome-based therapies are being developed. In the current study, we extensively characterize TIR-199, a syrbactin-class proteasome inhibitor derived from a plant virulence factor of bacterium Pseudomonas syringae pv syringae. We report that TIR-199 is a potent constitutive and immunoproteasome inhibitor, capable of inducing cell death in multiple myeloma, triple-negative breast cancer, (TNBC) and non-small cell lung cancer lines. TIR-199 also effectively inhibits the proteasome in primary myeloma cells of patients, and bypasses the PSMB5 A49T+A50V bortezomib-resistant mutant. TIR-199 treatment leads to accumulation of canonical proteasome substrates in cells, it is specific, and does not inhibit 50 other enzymes tested in vitro. The drug exhibits synergistic cytotoxicity in combination with proteasome-activating kinase DYRK2 inhibitor LDN192960. Furthermore, low-doses of TIR-199 exhibits in vivo activity by delaying myeloma-mediated bone degeneration in a mouse xenograft model. Together, our data indicates that proteasome inhibitor TIR-199 could indeed be a promising next-generation drug within the repertoire of proteasome-based therapeutics. 相似文献
Nucleocytoplasmic genetic conflicts arise as a result of asymmetric transmission of cytoplasmic and nuclear genes. Spread of a cytoplasmic element promoting female-biased sex ratios creates selection on nuclear genes for mechanisms that decrease the bias. Here we investigate the conflict over sex ratio between the cytoplasmic bacterium Wolbachia and the two-spotted spider mite Tetranychus urticae Koch. We show that, first, infected females produce significantly more female-biased sex ratios than uninfected (cured) females. Second, this effect is not due to parthenogenesis, male killing, or feminization, phenotypes commonly associated with infection by Wolbachia. Third, sex ratio is a trait with a heritable component in this species; thus, it can evolve under selection. Fourth, the sex ratio produced by uninfected (cured) females changes over time, approaching the sex ratio produced by females from the infected culture. On the basis of these results, we suggest that after sex ratio manipulation by Wolbachia, a host compensatory mechanism evolved that allows infected females to produce the sex ratio favored by nuclear genes. We discuss the evolution of "mutualism" with respect to the evolution of host mechanisms that compensate for effects induced by vertically transmitted "parasites." 相似文献
We examined induction of preference and performance on novel host plants for two laboratory populations of the polyphagous spider mite Tetranychus urticae, with one population adapted to bean and the other population adapted to tomato. We bred four isofemale lines of the bean population only and used them in all the assays. The bean population had a 30% lower fecundity on tomato than on bean, while the tomato population had equal fecundity on both host plants. Acclimation of adult females to the novel host plant for both populations increased acceptability of that novel host but did not increase rejection of the original host. The bean population experienced a 60% benefit and a 30% cost in terms of egg production for acclimating to tomato, thus exemplifying adaptive plasticity. The tomato population showed a 23% benefit for acclimating to bean but no cost. Mites from the bean population that were acclimated to tomato fed more on tomato than did mites that were not acclimated to tomato. When these mites were fed inhibitors of cytochrome P-450 detoxification enzymes, their performance was severely depressed (84%) on tomato but not on bean. However, mites that were fed inhibitors of P-450 enzymes did not reduce their acceptance of tomato as a host. Thus, performance on novel hosts (but not preference) in this species is likely correlated with the induction of detoxifying enzymes. Spider mites are known to form host races rapidly on novel hosts. Induction of preference and physiological acclimation via detoxification enzymes may enhance performance and, thus, strongly contribute to initial stages of host race formation. 相似文献
Wolbachia bacteria manipulate host reproduction by inducing cytoplasmic incompatibility (CI) and sex ratio distortion. Wolbachia
are transmitted from mother to offspring through the cytoplasm of the egg. Therefore, reproduction of Wolbachia is tightly
coupled to reproduction of its host. Mathematical analysis predicts that in the course of evolution, traits that reduce the
physiological costs of the infection will be selectively favored. For a Wolbachia-host system to evolve, traits under selection
must have some genetic component and variation must be present in the population. We have previously established that highly
inbred isofemale lines of the two-spotted spider mite Tetranychus urticae may differ regarding the effects of infection by Wolbachia, and that at least some of the traits affected had a genetic component.
However, the effects measured could have been affected by the fact that the lines were severely inbred prior to the experiments.
In this paper we attempt to distinguish between the effects of Wolbachia, isofemale line, and inbreeding. We show that Wolbachia
did not affect longevity but infected females produced smaller clutch sizes, more daughter-biased sex ratios and had decreased
F1 mortality; between-line variation was found for clutch size, F1 mortality and sex ratio; finally, inbreeding resulted in
an overall reduction of clutch sizes, and a change in survival curves and mean longevity.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
The purpose of this study was to evaluate the effects of L-4F, an apolipoprotein A-1 mimetic peptide, alone or with pravastatin, in apoE-/-Fas-/-C57BL/6 mice that spontaneously develop immunoglobulin G (IgG) autoantibodies, glomerulonephritis, osteopenia, and atherosclerotic lesions on a normal chow diet.
Methods
Female mice, starting at eight to nine weeks of age, were treated for 27 weeks with 1) pravastatin, 2) L-4F, 3) L-4F plus pravastatin, or 4) vehicle control, followed by disease phenotype assessment.
Results
In preliminary studies, dysfunctional, proinflammatory high-density lipoproteins (piHDL) were decreased six hours after a single L-4F, but not scrambled L-4F, injection in eight- to nine-week old mice. After 35 weeks, L-4F-treated mice, in the absence/presence of pravastatin, had significantly smaller lymph nodes and glomerular tufts (PL, LP < 0.05), lower serum levels of IgG antibodies to double stranded DNA (dsDNA) (PL < 0.05) and oxidized phospholipids (oxPLs) (PL, LP < 0.005), and elevated total and vertebral bone mineral density (PL, LP < 0.01) compared to vehicle controls. Although all treatment groups presented larger aortic root lesions compared to vehicle controls, enlarged atheromas in combination treatment mice had significantly less infiltrated CD68+ macrophages (PLP < 0.01), significantly increased mean α-actin stained area (PLP < 0.05), and significantly lower levels of circulating markers for atherosclerosis progression, CCL19 (PL, LP < 0.0005) and VCAM-1 (PL < 0.0002).
Conclusions
L-4F treatment, alone or with pravastatin, significantly reduced IgG anti-dsDNA and IgG anti-oxPLs, proteinuria, glomerulonephritis, and osteopenia in a murine lupus model of accelerated atherosclerosis. Despite enlarged aortic lesions, increased smooth muscle content, decreased macrophage infiltration, and decreased pro-atherogenic chemokines in L-4F plus pravastatin treated mice suggest protective mechanisms not only on lupus-like disease, but also on potential plaque remodeling in a murine model of systemic lupus erythematosus (SLE) and accelerated atherosclerosis. 相似文献
The emergence of multidrug-resistant (MDR) bacteria is a major challenge for antimicrobial chemotherapy. Concerning this issue, antimicrobial peptides (AMPs) have been presented as novel promising antibiotics. Our previous de novo designed melittin-derived peptides (MDP1 and MDP2) indicated their potential as peptide drug leads. Accordingly, this study was aimed to evaluate the kinetics of activity, toxicity, and stability of MDP1 and MDP2 as well as determination of their structures. The killing kinetics of MDP1 and MDP2 demonstrate that all bacterial strains were rapidly killed. MDP1 and MDP2 were ca. 100- and 26.6-fold less hemolytic than melittin and found to be respectively 72.9- and 41.6-fold less cytotoxic than melittin on the HEK293 cell line. MDP1 and MDP2 showed 252- and 132-fold improvement in their therapeutic index in comparison to melittin. MDP1 and MDP2 sustained their activities in the presence of human plasma and were found to be ca. four to eightfold more stable than melittin. Spectropolarimetry analysis of MDP1 and MDP2 indicates that the peptides adopt an alpha-helical structure predominantly. According to the fast killing kinetics, significant therapeutic index, and high stability of MDP1, it could be considered as a drug lead in a mouse model of septicemia infections.
Erv2p is an FAD-dependent sulfhydryl oxidase that can promote disulfide bond formation during protein biosynthesis in the yeast endoplasmic reticulum. The structure of Erv2p, determined by X-ray crystallography to 1.5 A resolution, reveals a helix-rich dimer with no global resemblance to other known FAD-binding proteins or thiol oxidoreductases. Two pairs of cysteine residues are required for Erv2p activity. The first (Cys-Gly-Glu-Cys) is adjacent to the isoalloxazine ring of the FAD. The second (Cys-Gly-Cys) is part of a flexible C-terminal segment that can swing into the vicinity of the first cysteine pair in the opposite subunit of the dimer and may shuttle electrons between substrate protein dithiols and the FAD-proximal disulfide. 相似文献
Erv2p is a small, dimeric FAD-dependent sulfhydryl oxidase that generates disulfide bonds in the lumen of the endoplasmic reticulum. Mutagenic and structural studies suggest that Erv2p uses an internal thiol-transfer relay between the FAD-proximal active site cysteine pair (Cys121-Cys124) and a second cysteine pair (Cys176-Cys178) located in a flexible, substrate-accessible C-terminal tail of the adjacent dimer subunit. Here, we demonstrate that Cys176 and Cys178 are the only amino acids in the tail region required for disulfide transfer and that their relative positioning within the tail peptide is important for activity. However, intragenic suppressor mutations could be isolated that bypass the requirement for Cys176 and Cys178. These mutants were found to disrupt Erv2p dimerization and to increase the activity of Erv2p for thiol substrates such as glutathione. We propose that the two Erv2p subunits act together to direct the disulfide transfer to specific substrates. One subunit provides the catalytic domain composed of the active site cysteine residues and the FAD cofactor, while the second subunit appears to have two functions: it facilitates disulfide transfer to substrates via the tail cysteine residues, while simultaneously shielding the active site cysteine residues from non-specific reactions. 相似文献