A New DNA‐Intercalative Cytotoxic Allylic Xanthone from Swertia corymbosa

Phytochemical investigation of the CHCl₃ fraction of Swertia corymbosa resulted in the isolation of a new 3‐allyl‐2,8‐dihydroxy‐1,6‐dimethoxy‐9H‐xanthen‐9‐one ( 1 ), along with four known xanthones, gentiacaulein ( 3 ), norswertianin ( 4 ), 1,3,6,8‐tetrahydroxyxanthone ( 5 ), and 1,3‐dihydroxyxanthone ( 6 ). Structure of compound 1 was elucidated with the aid of IR, UV, NMR, and MS data, and chemical transformation via new allyloxy xanthone derivative ( 2 ). Compounds 1 – 6 exhibited various levels of antioxidant and anti‐α‐glucosidase activities. Absorption and fluorescence spectroscopic studies on 1 – 6 indicated that these compounds could interact with calf thymus DNA (CT‐DNA) through intercalation and with bovine serum albumin (BSA) in a static quenching process. Compound 1 was found to be significantly cytotoxic against human cancer cell lines HeLa, HCT116, and AGS, and weakly active against normal NIH 3T3 cell line.     

Abnormal Red Cell Structure and Function in Neuroacanthocytosis

BackgroundPanthothenate kinase-associated neurodegeneration (PKAN) belongs to a group of hereditary neurodegenerative disorders known as neuroacanthocytosis (NA). This genetically heterogeneous group of diseases is characterized by degeneration of neurons in the basal ganglia and by the presence of deformed red blood cells with thorny protrusions, acanthocytes, in the circulation.ObjectiveThe goal of our study is to elucidate the molecular mechanisms underlying this aberrant red cell morphology and the corresponding functional consequences. This could shed light on the etiology of the neurodegeneration.MethodsWe performed a qualitative and semi-quantitative morphological, immunofluorescent, biochemical and functional analysis of the red cells of several patients with PKAN and, for the first time, of the red cells of their family members.ResultsWe show that the blood of patients with PKAN contains not only variable numbers of acanthocytes, but also a wide range of other misshapen red cells. Immunofluorescent and immunoblot analyses suggest an altered membrane organization, rather than quantitative changes in protein expression. Strikingly, these changes are not limited to the red blood cells of PKAN patients, but are also present in the red cells of heterozygous carriers without neurological problems. Furthermore, changes are not only present in acanthocytes, but also in other red cells, including discocytes. The patients’ cells, however, are more fragile, as observed in a spleen-mimicking device.ConclusionThese morphological, molecular and functional characteristics of red cells in patients with PKAN and their family members offer new tools for diagnosis and present a window into the pathophysiology of neuroacanthocytosis.     

Landscape of nuclear transport receptor cargo specificity

Nuclear transport receptors (NTRs) recognize localization signals of cargos to facilitate their passage across the central channel of nuclear pore complexes (NPCs). About 30 different NTRs constitute different transport pathways in humans and bind to a multitude of different cargos. The exact cargo spectrum of the majority of NTRs, their specificity and even the extent to which active nucleocytoplasmic transport contributes to protein localization remains understudied because of the transient nature of these interactions and the wide dynamic range of cargo concentrations. To systematically map cargo–NTR relationships in situ, we used proximity ligation coupled to mass spectrometry (BioID). We systematically fused the engineered biotin ligase BirA* to 16 NTRs. We estimate that a considerable fraction of the human proteome is subject to active nuclear transport. We quantified the specificity and redundancy in NTR interactions and identified transport pathways for cargos. We extended the BioID method by the direct identification of biotinylation sites. This approach enabled us to identify interaction interfaces and to discriminate direct versus piggyback transport mechanisms. Data are available via ProteomeXchange with identifier PXD007976.     

Structure and spatial patterns of trees in old-growth northern hardwood and mixed forests of northern Maine

Stand structure including spatial patterns was studied in northern hardwood and mixed forest types in the 2000-ha old-growth Big Reed Forest Reserve in northern Maine using complete stem mapping, dendrochronology, and spatial analyses on 0.5 plots. The inclusion of saplings, dead wood, age distributions, spatial pattern, and interactions provided some idea of underlying processes and temporal change. Structural characteristics were most comparable to spruce-northern hardwood forests of northern New England and New York, and most characteristics matched expected patterns for old-growth forests of the region.Results indicated smaller maximum-tree sizes, lower basal areas (26–34 ) and downed-wood volumes (29–64), higher densities (475–649), but similar species longevities compared to other mesic old-growth forests further south and in the Lake States. The stands were dominated by very shade-tolerant tree species, including Fagus grandifolia Ehrh., Acer saccharum Marsh.,Picea rubens Sarg. and Abies balsamea(L.) Mill, with each species found in many crown positions and age and size classes. The sapling layer was dominated by Fagus grandifolia followed by Picea rubens. Most species had reverse-J shaped diameter distributions, but age distributions were indicative of synchronous, episodic recruitment. In most plots, Acer saccharum diameter distributions were skewed towards the mid-larger size classes. Lack of young and small Acer saccharum stems suggested change in forest composition towards Fagus grandifolia dominance. Most species formed small-scale clusters (15 ) perhaps in response to small gap disturbances. Snags were the dominant dead wood type and were randomly to regularly distributed in most plots. Logfall directions were unrelated to hurricane paths. Recent small-scale disturbance events and topographic position appear to be important in explaining current structure and dynamics of the hardwood and mixed forests of Big Reed Forest Reserve in northern Maine. The continued effects of beech bark disease had a greater effect on hardwood plots, whereas a recent spruce budworm outbreak had a greater effect on plots with higher conifer density.The dominance of very shade tolerant tree species in small-scale clusters, and randomly distributed snags rather than clustered uproots were indicative of the prevalence of small scale gap disturbance regimes in the hardwood and mixed forests of Big Reed Forest Reserve in northern Maine. Varying topographic position may allow for slight changes in disturbance regime leading to consequent variation in structure and dynamics. H1, a more open plot on upper exposed slopes, had distinctly different characteristics such as lower live and dead tree and sapling densities than the other plots, but more uprooted trees and Acer saccharum saplings. Such small scale gap disturbance regimes operating on an episodic basis, and effects of slight variations in this regime on stand composition and structure have significant implications for silvicultural interventions and management of these forest types.     

A genome-wide association study of prostate cancer in West African men

Age-adjusted mortality rates for prostate cancer are higher for African-American men compared with those of European ancestry. Recent data suggest that West African men also have elevated risk for prostate cancer relative to European men. Genetic susceptibility to prostate cancer could account for part of this difference. We conducted a genome-wide association study (GWAS) of prostate cancer in West African men in the Ghana Prostate Study. Association testing was performed using multivariable logistic regression adjusted for age and genetic ancestry for 474 prostate cancer cases and 458 population-based controls on the Illumina HumanOmni-5 Quad BeadChip. The most promising association was at 10p14 within an intron of a long non-coding RNA (lncRNA RP11-543F8.2) 360 kb centromeric of GATA3 (p = 1.29E?7). In sub-analyses, SNPs at 5q31.3 were associated with high Gleason score (≥7) cancers, the strongest of which was a missense SNP in PCDHA1 (rs34575154, p = 3.66E?8), and SNPs at Xq28 (rs985081, p = 8.66E?9) and 6q21 (rs2185710, p = 5.95E?8) were associated with low Gleason score (<7) cancers. We sought to validate our findings in silico in the African Ancestry Prostate Cancer GWAS Consortium, but only one SNP, at 10p14, replicated at p < 0.05. Of the 90 prostate cancer loci reported from studies of men of European, Asian or African-American ancestry, we were able to test 81 in the Ghana Prostate Study, and 10 of these replicated at p < 0.05. Further genetic studies of prostate cancer in West African men are needed to confirm our promising susceptibility loci.     

Fire, People and Pixels: Linking Social Science and Remote Sensing to Understand Underlying Causes and Impacts of Fires in Indonesia

This study in the wake of 1990s fire catastrophes identifies and analyzes underlying causes of vegetation fires in eight locations across Borneo and Sumatra. Multidisciplinary and multiscale analysis integrates geospatial technologies with varied social research approaches and participatory mapping. It helps fill a void of site-specific evidence on diverse underlying causes of the Indonesian fires, despite emerging consensus on macrolevel causes and impacts, and policy debates on preventing future fire disasters. Our most important findings include confirmation of multiple direct and underlying fire causes at each of the eight locations, no single dominant fire cause at any site, and wide differences in fire causes among sites. Conclusions emphasize the importance of location specific studies within a regional analytical context. Our “hybrid” research methods demonstrate the explanatory power of integrating geospatial and social analysis techniques, and the benefits of analyzing fire causes and impacts at multiple scales in varied locations across diverse regions.     

SNP Association Mapping across the Extended Major Histocompatibility Complex and Risk of B-Cell Precursor Acute Lymphoblastic Leukemia in Children

The extended major histocompatibility complex (xMHC) is the most gene-dense region of the genome and harbors a disproportionately large number of genes involved in immune function. The postulated role of infection in the causation of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) suggests that the xMHC may make an important contribution to the risk of this disease. We conducted association mapping across an approximately 4 megabase region of the xMHC using a validated panel of single nucleotide polymorphisms (SNPs) in childhood BCP-ALL cases (n=567) enrolled in the Northern California Childhood Leukemia Study (NCCLS) compared with population controls (n=892). Logistic regression analyses of 1,145 SNPs, adjusted for age, sex, and Hispanic ethnicity indicated potential associations between several SNPs and childhood BCP-ALL. After accounting for multiple comparisons, one of these included a statistically significant increased risk associated with rs9296068 (OR=1.40, 95% CI=1.19-1.66, corrected p=0.036), located in proximity to HLA-DOA. Sliding window haplotype analysis identified an additional locus located in the extended class I region in proximity to TRIM27 tagged by a haplotype comprising rs1237485, rs3118361, and rs2032502 (corrected global p=0.046). Our findings suggest that susceptibility to childhood BCP-ALL is influenced by genetic variation within the xMHC and indicate at least two important regions for future evaluation.