Membrane topological model of glycosyltransferases of the GT-C superfamily

Glycosyltransferases that use polyisoprenol-linked donor substrates are categorized in the GT-C superfamily. In eukaryotes, they act in the endoplasmic reticulum (ER) lumen and are involved in N-glycosylation, glypiation, O-mannosylation, and C-mannosylation of proteins. We generated a membrane topology model of C-mannosyltransferases (DPY19 family) that concurred perfectly with the 13 transmembrane domains (TMDs) observed in oligosaccharyltransferases (STT3 family) structures. A multiple alignment of family members from diverse organisms highlighted the presence of only a few conserved amino acids between DPY19s and STT3s. Most of these residues were shown to be essential for DPY19 function and are positioned in luminal loops that showed high conservation within the DPY19 family. Multiple alignments of other eukaryotic GT-C families underlined the presence of similar conserved motifs in luminal loops, in all enzymes of the superfamily. Most GT-C enzymes are proposed to have an uneven number of TDMs with 11 (POMT, TMTC, ALG9, ALG12, PIGB, PIGV, and PIGZ) or 13 (DPY19, STT3, and ALG10) membrane-spanning helices. In contrast, PIGM, ALG3, ALG6, and ALG8 have 12 or 14 TMDs and display a C-terminal dilysine ER-retrieval motif oriented towards the cytoplasm. We propose that all members of the GT-C superfamily are evolutionary related enzymes with preserved membrane topology

Navigating the garden of forking paths for data exclusions in fear conditioning research

In this report, we illustrate the considerable impact of researcher degrees of freedom with respect to exclusion of participants in paradimgs with a learning element. We illustrate this empirically through case examples from human fear conditioning research where the exclusion of ‘non-learners’ and ‘non-responders’ is common-despite a lack of consensus on how to define these groups. We illustrate the substantial heterogeneity in exclusion criteria based on a systematic literature search and highlight potential problems and pitfalls of different definitions through case examples based on re-analyses of existing data sets. Based on this, we propose a consensus on evidence-based rather than idiosyncratic criteria including clear guidelines on reporting details. Taken together, we illustrate how flexibility in data collection and analysis can be avoided, which will benefit the robustness and replicability of research findings and can be expected to be applicable to other fields of research that involve a learning element

Subduction controls of Hf and Nd isotopes in lavas of the Aleutian island arc

The Hf and Nd isotopic compositions of 71 Quaternary lavas collected from locations along the full length of the Aleutian island arc are used to constrain the sources of Aleutian magmas and to provide insight into the geochemical behavior of Nd and Hf and related elements in the Aleutian subduction-magmatic system. Isotopic compositions of Aleutian lavas fall approximately at the center of, and form a trend parallel to, the terrestrial Hf-Nd isotopic array with {var_epsilon}{sub Hf} of +12.0 to +15.5 and {var_epsilon}{sub Nd} of +6.5 to +10.5. Basalts, andesites, and dacites within volcanic centers or in nearby volcanoes generally all have similar isotopic compositions, indicating that there is little measurable effect of crustal or other lithospheric assimilation within the volcanic plumbing systems of Aleutian volcanoes. Hafnium isotopic compositions have a clear pattern of along-arc increase that is continuous from the eastern-most locations near Cold Bay to Piip Seamount in the western-most part of the arc. This pattern is interpreted to reflect a westward decrease in the subducted sediment component present in Aleutian lavas, reflecting progressively lower rates of subduction westward as well as decreasing availability of trench sediment. Binary bulk mixing models (sediment + peridotite) demonstrate that 1-2% of the Hf in Aleutian lavas is derived from subducted sediment, indicating that Hf is mobilized out of the subducted sediment with an efficiency that is similar to that of Sr, Pb and Nd. Low published solubility for Hf and Nd in aqueous subduction fluids lead us to conclude that these elements are mobilized out of the subducted component and transferred to the mantle wedge as bulk sediment or as a silicate melt. Neodymium isotopes also generally increase from east to west, but the pattern is absent in the eastern third of the arc, where the sediment flux is high and increases from east to west, due to the presence of abundant terrigenous sediment in the trench east of the Amlia Fracture Zone, which is being subducting beneath the arc at Seguam Island. Mixing trends between mantle wedge and sediment end members become flatter in Hf-Nd isotope space at locations further west along the arc, indicating that the sediment end member in the west has either higher Nd/Hf or is more radiogenic in Hf compared to Nd. This pattern is interpreted to reflect an increase in pelagic clay relative to the terrigenous subducted sedimentary component westward along the arc. Results of this study imply that Hf does not behave as a conservative element in the Aleutian subduction system, as has been proposed for some other arcs

Submarine back-arc lava with arc signature : Fonualei Spreading Center, northeast Lau Basin, Tonga

Author Posting. © American Geophysical Union, 2008. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 113 (2008): B08S07, doi:10.1029/2007JB005451.We present major, volatile, and trace elements for quenched glasses from the Fonualei Spreading Center, a nascent spreading system situated very close to the Tofua Volcanic Arc (20 km at the closest), in the northeast Lau Basin. The glasses are basalts and basaltic andesites and are inferred to have originated from a relatively hot and depleted mantle wedge. The Fonualei Spreading Center shows island arc basalt (IAB) affinities, indistinguishable from the Tofua Arc. Within the Fonualei Spreading Center no geochemical trends can be seen with depth to the slab and/or distance to the arc, despite a difference in depth to the slab of >50 km. Therefore we infer that all the subduction-related magmatism is captured by the back arc as the adjacent arc is shut off. There is a sharp contrast between the main spreading area of the Fonualei Spreading Center (FSC) and its northernmost termination, the Mangatolu Triple Junction (MTJ). The MTJ samples are characteristic back-arc basin basalts (BABB). We propose that the MTJ and FSC have different mantle sources, reflecting different mantle origins and/or different melting processes. We also document a decrease in mantle depletion from the south of the FSC to the MTJ, which is the opposite to what has been documented for the rest of the Lau Basin where depletion generally increases from south to north. We attribute this reverse trend to the influx of less depleted mantle through the tear between the Australian and the Pacific plates, at the northern boundary of the Lau Basin.NSK acknowledges the support of an A.E. Ringwood Scholarship from the RSES

Decreased expression of 17β-hydroxysteroid dehydrogenase type 1 is associated with DNA hypermethylation in colorectal cancer located in the proximal colon

<p>Abstract</p> <p>Background</p> <p>The importance of 17β-estradiol (E2) in the prevention of large bowel tumorigenesis has been shown in many epidemiological studies. Extragonadal E2 may form by the aromatase pathway from androstenedione or the sulfatase pathway from estrone (E1) sulfate followed by E1 reduction to E2 by 17-β-hydroxysteroid dehydrogenase (HSD17B1), so <it>HSD17B1 </it>gene expression may play an important role in the production of E2 in peripheral tissue, including the colon.</p> <p>Methods</p> <p><it>HSD17B1 </it>expression was analyzed in colorectal cancer cell lines (HT29, SW707) and primary colonic adenocarcinoma tissues collected from fifty two patients who underwent radical colon surgical resection. Histopathologically unchanged colonic mucosa located at least 10-20 cm away from the cancerous lesions was obtained from the same patients. Expression level of <it>HSD17B1 </it>using quantitative PCR and western blot were evaluated. DNA methylation level in the 5' flanking region of <it>HSD17B1 </it>CpG rich region was assessed using bisulfite DNA sequencing and HRM analysis. The influence of DNA methylation on HSD17B1 expression was further evaluated by ChIP analysis in HT29 and SW707 cell lines. The conversion of estrone (E1) in to E2 was determined by electrochemiluminescence method.</p> <p>Results</p> <p>We found a significant decrease in HSD17B1 transcript (<it>p </it>= 0.0016) and protein (<it>p </it>= 0.0028) levels in colorectal cancer (CRC) from the proximal but not distal colon and rectum. This reduced <it>HSD17B1 </it>expression was associated with significantly increased DNA methylation (<it>p </it>= 0.003) in the CpG rich region located in the 5' flanking sequence of the <it>HSD17B1 </it>gene in CRC in the proximal but not distal colon and rectum. We also showed that 5-dAzaC induced demethylation of the 5' flanking region of <it>HSD17B1</it>, leading to increased occupation of the promoter by Polymerase II, and increased transcript and protein levels in HT29 and SW707 CRC cells, which contributed to the increase in E2 formation.</p> <p>Conclusions</p> <p>Our results showed that reduced <it>HSD17B1 </it>expression can be associated with DNA methylation in the 5' flanking region of <it>HSD17B1 </it>in CRC from the proximal colon.</p

The association between weight at birth and breast cancer risk revisited using Mendelian randomisation.

Observational studies suggest that higher birth weight (BW) is associated with increased risk of breast cancer in adult life. We conducted a two-sample Mendelian randomisation (MR) study to assess whether this association is causal. Sixty independent single nucleotide polymorphisms (SNPs) known to be associated at P < 5 × 10-8 with BW were used to construct (1) a 41-SNP instrumental variable (IV) for univariable MR after removing SNPs with pleiotropic associations with other breast cancer risk factors and (2) a 49-SNP IV for multivariable MR after filtering SNPs for data availability. BW predicted by the 41-SNP IV was not associated with overall breast cancer risk in inverse-variance weighted (IVW) univariable MR analysis of genetic association data from 122,977 breast cancer cases and 105,974 controls (odds ratio = 0.86 per 500 g higher BW; 95% confidence interval 0.73-1.01). Sensitivity analyses using four alternative methods and three alternative IVs, including an IV with 59 of the 60 BW-associated SNPs, yielded similar results. Multivariable MR adjusting for the effects of the 49-SNP IV on birth length, adult height, adult body mass index, age at menarche, and age at menopause using IVW and MR-Egger methods provided estimates consistent with univariable analyses. Results were also similar when all analyses were repeated after restricting to estrogen receptor-positive or -negative breast cancer cases. Point estimates of the odds ratios from most analyses performed indicated an inverse relationship between genetically-predicted BW and breast cancer, but we are unable to rule out an association between the non-genetically-determined component of BW and breast cancer. Thus, genetically-predicted higher BW was not associated with an increased risk of breast cancer in adult life in our MR study

Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk

Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk

An Antimicrobial Peptide Regulates Tumor-Associated Macrophage Trafficking via the Chemokine Receptor CCR2, a Model for Tumorigenesis

Tumor-associated macrophages (TAMs) constitute a significant part of infiltrating inflammatory cells that are frequently correlated with progression and poor prognosis of a variety of cancers. Tumor cell-produced human β-defensin-3 (hBD-3) has been associated with TAM trafficking in oral cancer; however, its involvement in tumor-related inflammatory processes remains largely unknown., applying a cross-desensitization strategy of CCR2 and its pharmacological inhibitor (RS102895), respectively, was also carried out. outcome and demonstrates the importance of the innate immune system in the development of tumors