Metabolic QTL Analysis Links Chloroquine Resistance in Plasmodium falciparum to Impaired Hemoglobin Catabolism

Drug resistant strains of the malaria parasite, Plasmodium falciparum, have rendered chloroquine ineffective throughout much of the world. In parts of Africa and Asia, the coordinated shift from chloroquine to other drugs has resulted in the near disappearance of chloroquine-resistant (CQR) parasites from the population. Currently, there is no molecular explanation for this phenomenon. Herein, we employ metabolic quantitative trait locus mapping (mQTL) to analyze progeny from a genetic cross between chloroquine-susceptible (CQS) and CQR parasites. We identify a family of hemoglobin-derived peptides that are elevated in CQR parasites and show that peptide accumulation, drug resistance, and reduced parasite fitness are all linked in vitro to CQR alleles of the P. falciparum chloroquine resistance transporter (pfcrt). These findings suggest that CQR parasites are less fit because mutations in pfcrt interfere with hemoglobin digestion by the parasite. Moreover, our findings may provide a molecular explanation for the reemergence of CQS parasites in wild populations.     

Disruption of Clathrin‐Mediated Trafficking Causes Centrosome Overduplication and Senescence

The Hsc70 cochaperone, G cyclin‐associated kinase (GAK), has been shown to be essential for the chaperoning of clathrin by Hsc70 in the cell. In this study, we used conditional GAK knockout mouse embryonic fibroblasts (MEFs) to determine the effect of completely inhibiting clathrin‐dependent trafficking on the cell cycle. After GAK was knocked out, the cells developed the unusual phenotype of having multiple centrosomes, but at the same time failed to divide and ultimately became senescent. To explain this phenotype, we examined the signaling profile and found that mitogenic stimulation of the GAK KO cells and the control cells were similar except for increased phosphorylation of Akt. In addition, the disruption of intracellular trafficking caused by knocking out GAK destabilized the lysosomal membranes, resulting in DNA damage due to iron leakage. Knocking down clathrin heavy chain or inhibiting dynamin largely reproduced the GAK KO phenotype, but inhibiting only clathrin‐mediated endocytosis by knocking down adaptor protein (AP2) caused growth arrest and centrosome overduplication, but no DNA damage or senescence. We conclude that disruption of clathrin‐dependent trafficking induces senescence accompanied by centrosome overduplication because of a combination of DNA damage and changes in mitogenic signaling that uncouples centrosomal duplication from DNA replication.     

Shape and volume of craniofacial cavities in intentional skull deformations

Intentional cranial deformations (ICD) have been observed worldwide but are especially prevalent in preColombian cultures. The purpose of this study was to assess the consequences of ICD on three cranial cavities (intracranial cavity, orbits, and maxillary sinuses) and on cranial vault thickness, in order to screen for morphological changes due to the external constraints exerted by the deformation device. We acquired CT‐scans for 39 deformed and 19 control skulls. We studied the thickness of the skull vault using qualitative and quantitative methods. We computed the volumes of the orbits, of the maxillary sinuses, and of the intracranial cavity using haptic‐aided semi‐automatic segmentation. We finally defined 3D distances and angles within orbits and maxillary sinuses based on 27 anatomical landmarks and measured these features on the 58 skulls. Our results show specific bone thickness patterns in some types of ICD, with localized thinning in regions subjected to increased pressure and thickening in other regions. Our findings confirm that volumes of the cranial cavities are not affected by ICDs but that the shapes of the orbits and of the maxillary sinuses are modified in circumferential deformations. We conclude that ICDs can modify the shape of the cranial cavities and the thickness of their walls but conserve their volumes. These results provide new insights into the morphological effects associated with ICDs and call for similar investigations in subjects with deformational plagiocephalies and craniosynostoses. Am J Phys Anthropol 151:110–119, 2013. © 2013 Wiley Periodicals, Inc.     

Notes on ecotone attributes and functions

We attempt to identify general properties of ecotones. Earlier attempts to do so encountered difficulties resulting from contradictory conceptions of ecotones. Thus, we begin with and center our discussion on a definition of ecotone. The definition is complex. It includes scaling, structural, and functional aspects. Based on this complex definition, we offer a brief review of what is an ecotone, what attributes it has, and how it influences other habitats of interest. We identify feedback as a possibly important but ignored function of ecotones. This discussion is presented in general terms which apply to a variety of ecological situations. We point out that results of an evaluation of ecotone attributes largely depends on the spatial and temporal scale at which ecotone is conceptualized and data are collected. We suggest that some of ecotone determinants scale naturally in a repeatable fashion among various aquatic systems. Finally, we point to the concentration of dynamic properties of ecotones as applied to land/water interface.     

Sequence stratigraphy of an Upper Pennsylvanian,Midcontinent cyclothem from north America (Iola Limestone,Kansas and Missouri,USA)

Summary The Iola Limestone is the open-marine, carbonate portion of a Midcontinent cyclothem. It represents the transgressive and highstand systems tracts of a stratigraphic sequence. The sequence begins with a type 1 sequence boundary at the base of the Chanute Shale, which underlies the Iola. This surface can be recognized by the presence of a paleosol and as much as 15 m of incision. Part of the Chanute is probably an estuarine valley-fill package and represents the lowstand systems tract. The lowest member of the Iola Limestone is the Paola Limestone Member. Its base is sharp and locally has a thin shell lag. This contact is the transgressive surface and represents the onset of open-marine, clear-water carbonate sedimentation. It is a ravinement surface cut by a winnowing environment that appears as a ‘kink’ in the base-level surface. Landward of this ‘kink’, sediment accumulated to a subaerial base-level, but seaward of it sediment did not accumulate above a subtidal threshold probably controlled by wave base. Facies formed during regression also show the influence of a ‘kink’ in base-level. The Paola itself is the lower part of the transgressive facies tract. Overlying the Paola is the Muncie Creck Shale Member; its lower part is black and fissile, contains phosphate nodules, no unequivocally benthic fossils, and no discernible trace fossils. However, this facies is not present everywhere; in much of southeastern Kansas and just north of Kansas City, Missouri, it has been removed by submarine erosion. The only clues that this facies was ever deposited are reworked diagenetic phosphate nodules that occur as a lag on a hardground on top of the Paola. Where black shale and the immediately overlying, relatively unfossiliferous gray shale have been preserved, they are overlain by a shelly lag that incorporates bored and encrusted micritic cobbles-strong evidence of reworking. This erosional surface is interpreted as the maximum flooding surface. Such an interpretation suggests that the black shale formed during sea-level rise and coastal transgression rather than at sea-level highstand. This is further supported by geochemical properties of Midcontinent black shales. Overlying the maximum flooding surface are a thin gray shale (within the Muncie Creek) and the Raytown Lime-stone Member. In southern Kansas, the limestone contains an extensive phylloid-algal mound. In the subsurface, the elongate Raytown mound is perpendicular to the outcrop belt; it directly overlies a Precambrian structural element called the Bourbon arch, suggesting subtle tectonic control. In northern Missouri and in Nebraska, the upper Raytown contains carbonate tidal-flat deposits. The existence of these two facies suggests that the Raytown was deposited while base-level was stable rather than during base-level drop. The aggradational algal mound built into a positive sea-floor feature and did not shift position through the duration of the cycle. Progradational carbonate tidal flats had the chance to develop in the northern part of the field area; if base-level had been dropping, rapid regression would likely not have permitted accumulation of this facies at the top of the limestone. Coarse-grained deposits, an oncolite in southern Kansas and bioclastic packstones and grainstones in northern Kansas, indicate that the mound aggraded up to a subtidal base-level, presumably controlled by wave base. The carbonate tidal flats, on the other hand, filled accommodation space up to a subaerial base-level as they prograded out over this surface. There must have been two base-levels—one subtidal and the other subaerial—connected by the previously mentioned base-level ‘kink’ at the coastline. The Lane Shale, typically gray-green and silty, overlies the Iola. In a core from northern Missouri, the Lane Shale directly overlying the Raytown contains clay slickensides and a breccia of ‘fitted’ carbonate clasts, indicating subaerial exposure and qualifying the base of the Lane Shale as the top boundary of the Iola sequence. In northwestern Missouri, the Iola changes from a relatively clay-free limestone to mostly dark-gray, calcareous mudrocks with thin shell stringers. This represents a part of the basin dominated by clastic input. Stratigraphic interpretation implies that the Muncie Creek black shale formed during accommodation space increase and shoreline transgression. This is consistent with recent geochemical studies of Midcontinent black shales. This lithology formed as inland peat swamps underwent ravinement and organic matter was flushed onto the shelf. An influx of nutrients and plant material made available by sea-level rise and transgression while sediment was trapped in nearshore accommodation space was the primary cause of sediment starvation and anoxia in the basin.     

Isolation and characterization of abscisic acid-deficient Arabidopsis mutants at two new loci

Novel Arabidopsis mutants with lowered levels of endogenous abscisic acid (ABA) were isolated. These were selected in a screen for germination in the presence of the gibberellin biosynthesis inhibitor paclobutrazol. Another mutant was isolated in a screen for NaCl tolerance. The ABA-deficiency was caused by two monogenic, recessive mutations, aba2 and aba3 , that were both located on chromosome 1. The mutants showed a phenotype that is known to be characteristic for ABA-deficiency: a reduced seed dormancy and excessive water loss, leading to a wilty phenotype. Double mutant analysis, combining different aba mutations, indicated the leaky nature of the mutations.     

Antibody titers by mixed agglutination to varicella-zoster, herpes simplex and vaccinia viruses in patients with multiple sclerosis.

Antibody titers to varicella-zoster (V-Z), herpes simplex (HSV) and vaccinia viruses were determined in sera collected in Buffalo, NY, from patients with multiple sclerosis (MS), patients with other diseases, and normal individuals. The mixed agglutination test employing cell cultures infected with one of the above viruses as a source of antigen was used to determine antibody titers. The geometric mean titer (GMT) for V-Z in 59 MS cases was significantly higher than that observed in patients with other diseases and in normal individuals. The GMT for vaccinia was also higher in MS patients but the difference was not as great as for V-Z. No difference was observed in the titer of antibodies for HSV. Similar results were obtained for 51 MS patients compared to healthy controls matched for sex and age. Higher antibody titers for V-Z and HSV were observed in cerebrospinal fluids from MS cases than in those from non-MS CNS patients in Baltimore, MD. Antibodies to V-Z, HSV and vaccinia were detected in washing fluids from brain homogenates of MS cases.