Contributions of chaperone and glycosyltransferase activities of O-fucosyltransferase 1 to Notch signaling

<p>Abstract</p> <p>Background</p> <p><it>O</it>-fucosyltransferase1 (OFUT1) is a conserved ER protein essential for Notch signaling. OFUT1 glycosylates EGF domains, which can then be further modified by the <it>N</it>-acetylglucosaminyltransferase Fringe. OFUT1 also possesses a chaperone activity that promotes the folding and secretion of Notch. Here, we investigate the respective contributions of these activities to Notch signaling in <it>Drosophila</it>.</p> <p>Results</p> <p>We show that expression of an isoform lacking fucosyltransferase activity, <it>Ofut1</it>^{<it>R</it>245<it>A</it>}, rescues the requirement for <it>Ofut1 </it>in embryonic neurogenesis. Lack of requirement for <it>O</it>-fucosylation is further supported by the absence of embryonic phenotypes in <it>Gmd </it>mutants, which lack all forms of fucosylation. Requirements for <it>O</it>-fucose during imaginal development were evaluated by characterizing clones of cells expressing only <it>Ofut1</it>^{<it>R</it>245<it>A</it>}. These clones phenocopy <it>fringe </it>mutant clones, indicating that the absence of <it>O</it>-fucose is functionally equivalent to the absence of elongated <it>O</it>-fucose.</p> <p>Conclusion</p> <p>Our results establish that Notch does not need to be <it>O</it>-fucosylated for <it>fringe</it>-independent Notch signaling in <it>Drosophila</it>; the chaperone activity of OFUT1 is sufficient for the generation of functional Notch.</p

Patterns in freshwater diatom taxonomic distinctness along an eutrophication gradient

This is the peer reviewed version of the following article: Leira, M., Chen, G., Dalton, C., Irvine, K. and Taylor, D., 2009. Patterns in freshwater diatom taxonomic distinctness along an eutrophication gradient. Freshwater Biology, 54(1), pp.1-14., which has been published in final form at https://doi.org/10.1111/j.1365-2427.2008.02086.x1. A variety of species richness measures have been used to assess the effects of environmental degradation on biodiversity. Such measures can be highly influenced by sample size, sampling effort, habitat type or complexity, however, and typically do not show monotonic responses to human impact. In addition to being independent of the degree of sampling effort involved in data acquisition, effective measures of biodiversity should reflect the degree of taxonomical relatedness among species within ecological assemblages and provide a basis for understanding observed diversity for a particular habitat type. Taxonomic diversity or distinctness indices emphasize the average taxonomic relatedness (i.e. degree of taxonomical closeness) between species in a community. 2. Eutrophication of freshwater ecosystems, mainly due to the increased availability of nutrients, notably phosphorus, has become a major environmental problem. Two measures of taxonomic distinctness (Average Taxonomic Distinctness and Variation in Taxonomic Distinctness) were applied to surface sediment diatoms from 45 lakes across the island of Ireland to examine whether taxonomic distinctness and nutrient enrichment were significantly related at a regional scale. The lakes span a range of concentrations of epilimnic total phosphorus (TP) and were grouped into six different types, based on depth and alkalinity levels, and three different categories according to trophic state (ultra-oligotrophic and oligotrophic; mesotrophic; and eutrophic and hyper-eutrophic). 3. The taxonomic distinctness measures revealed significant differences among lakes in the three different classes of trophic state, with nutrient-rich lakes generally more taxonomically diverse than nutrient-poor lakes. This implies that enrichment of oligotrophic lakes does not necessarily lead to a reduction in taxonomic diversity, at least as expressed by the indices used here. Furthermore, taxonomic distinctness was highly variable across the six different lake types regardless of nutrient level. 4. Results indicate that habitat availability and physical structure within the study lakes also exert a strong influence on the pattern of taxonomic diversity. Overall the results highlight problems with the use of taxonomic diversity measures for detecting impacts of freshwater eutrophication based on diatom assemblages.The present study is based on material and data collected as part of the EPA Ireland-funded IN-SIGHT Project (# 2002-W-LS/7) and through a separate doctoral scholarship awarded by the same agency to G. Chen (#2002_PHD2_34). We would like to thank in particular Jim Bowman of the EPA. Thanks are also due to several staff and postgraduate research students from UU Coleraine and Trinity College, University of Dublin, most notably Phil Jordan and Richard McFaul, for assistance with fieldwork. Sergi Sabater provided constructive suggestions for the manuscript.S

Rapid ecosystem recovery from diffuse pollution after the Great Irish Famine

This is an Accepted Manuscript of an article published by Taylor & Francis in Ecological Applications on September 2010, available at: https://doi.org/10.1890/09-1966.1Remarkably little is known about the effectiveness or rates of recovery of aquatic ecosystems from reductions in human-associated pressures at landscape scales. The retention of anthropogenic contaminants within ecosystems can retard rates of recovery considerably, while the trajectories of recovery processes vary with the extent of disturbance and the resilience of biotic assemblages. The Great Irish Famine of 1845-1850 comprised one of the most significant human disasters of the 19th century, causing the death of approximately one million people and the emigration of a further two million from the country between 1845 and 1855. We found, through analysis of detailed historical census data combined with paleolimnological investigation of sedimentary nutrient concentrations, stable isotope ratios, and diatom assemblages, that the trophic level of Lough Carra, a largely shallow calcareous lake in the west of Ireland with no urban areas or point sources of any significance in its catchment, reduced considerably during and immediately after the Great Famine, shifting to new equilibria within just 2-10 years. Our results demonstrate that the reduction of human pressures from diffuse sources at landscape scales can result in the rapid and monotonie recovery of aquatic ecosystems. Moreover, the recovery of ecosystems from diffuse pollution need not necessarily take longer than recovery from pollution from point sources.S

Yorkie Promotes Transcription by Recruiting a Histone Methyltransferase Complex

SummaryHippo signaling limits organ growth by inhibiting the transcriptional coactivator Yorkie. Despite the key role of Yorkie in both normal and oncogenic growth, the mechanism by which it activates transcription has not been defined. We report that Yorkie binding to chromatin correlates with histone H3K4 methylation and is sufficient to locally increase it. We show that Yorkie can recruit a histone methyltransferase complex through binding between WW domains of Yorkie and PPxY sequence motifs of NcoA6, a subunit of the Trithorax-related (Trr) methyltransferase complex. Cell culture and in vivo assays establish that this recruitment of NcoA6 contributes to Yorkie’s ability to activate transcription. Mammalian NcoA6, a subunit of Trr-homologous methyltransferase complexes, can similarly interact with Yorkie’s mammalian homolog YAP. Our results implicate direct recruitment of a histone methyltransferase complex as central to transcriptional activation by Yorkie, linking the control of cell proliferation by Hippo signaling to chromatin modification

Effects of flow alteration on Apple-ring Acacia (Faidherbia albida) stands, Middle Zambezi floodplains, Zimbabwe

The impounding of the Zambezi River by Kariba dam has regulated the river discharge of the Middle Zambezi river. This has been implicated in the failure of regeneration of Faidherbia albida in the downstream flood plain. This study aimed (1) to assess the effect of the altered flow regime of the river on the establishment and growth of F. albida on the Middle Zambezi floodplain and islands and (2) to test the potential of dendrochronology in detecting the age and long-term growth rates of F. albida in response to flow regime. Results indicated an uneven age distribution of F. albida stands on relatively ‘new islands’, dominated by young trees, while the floodplain and the ‘old island’ exhibited an even-aged stand but with a lack of regeneration, and a dying-off of older trees. The lack of F. albida establishment on the floodplain was linked to the decreased occurrence of flooding events, associated with a decrease in alluvial deposits, soil moisture and groundwater recharge. These effects may be enhanced by impact from browsers on regeneration of trees. Tree-ring analyses revealed the presence of distinct annual growth rings in F. albida and the applicability of dendrochronology for estimating F. albida population dynamics. The trees on the ‘new islands’ are younger and grow faster than those on the floodplain. Lack of competition and possible favourable moisture conditions suggest beneficial conditions for establishment and growth of the trees on the islands

Choice of Antiretroviral Drugs for Postexposure Prophylaxis for Adults and Adolescents: A Systematic Review

Background. The choice of preferred regimens for human immunodeficiency virus postexposure prophylaxis (PEP) has evolved over the last 2 decades as more data have become available regarding the safety and tolerability of newer antiretroviral drugs. We undertook a systematic review to assess the safety and efficacy of antiretroviral options for PEP to inform the World Health Organization guideline revision process. Methods. Four databases were searched up to 1 June 2014 for studies reporting outcomes associated with specific PEP regimens. Data on PEP completion and discontinuation due to adverse events was extracted and pooled estimates were obtained using random-effects meta-analyses. Results. Fifteen studies (1830 PEP initiations) provided evaluable information on 2-drug regimens (zidovudine [ZDV]- or tenofovir [TDF]-based regimens), and 10 studies (1755 initiations) provided evaluable information on the third drug, which was usually a protease inhibitor. The overall quality of the evidence was rated as very low. For the 2-drug regimen, PEP completion rates were 78.4% (95% confidence interval [CI], 66.1%-90.7%) for people receiving a TDF-based regimen and 58.8% (95% CI, 47.2%-70.4%) for a ZDV-based regimen; the rate of PEP discontinuation due to an adverse event was lower among people taking TDF-based PEP (0.3%; 95% CI, 0%-1.1%) vs a ZDV-based regimen (3.2%; 95% CI, 1.5%-4.9%). For the 3-drug comparison, PEP completion rates were highest for the TDF-based regimens (TDF+emtricitabine [FTC]+lopinavir/ritonavir [LPV/r], 71.1%; 95% CI, 43.6%-98.6%; TDF+FTC+raltegravir [RAL], 74.7%; 95% CI, 41.4%-100%; TDF+FTC+ boosted darunavir [DRV/r], 93.9%; 95% CI, 90.2%-97.7%) and lowest for ZDV+ lamivudine [3TC]+LPV/r (59.1%; 95% CI, 36.2%-82.0%). Discontinuations due to adverse drug reactions were lowest for TDF+FTC+RAL (1.9%; 95% CI, 0%-3.8%) and highest for ZDV+3TC+boosted atazanavir (21.2%; 95% CI, 13.5%-30.0%). Conclusions. The findings of this review provide evidence supporting the use of coformulated TDF and 3TC/FTC as preferred backbone drugs for PEP. Choice of third drug will depend on setting; for resource-limited settings, LPV/r is a reasonable choice, pending the improved availability of better-tolerated drugs with less potential for drug-drug interaction

Capacity challenges in water quality monitoring: understanding the role of human development

Monitoring the qualitative status of freshwaters is an important goal of the international community, as stated in the Sustainable Development Goal (SDGs) indicator 6.3.2 on good ambient water quality. Monitoring data are, however, lacking in many countries, allegedly because of capacity challenges of less-developed countries. So far, however, the relationship between human development and capacity challenges for water quality monitoring have not been analysed systematically. This hinders the implementation of fine-tuned capacity development programmes for water quality monitoring. Against this background, this study takes a global perspective in analysing the link between human development and the capacity challenges countries face in their national water quality monitoring programmes. The analysis is based on the latest data on the human development index and an international online survey amongst experts from science and practice. Results provide evidence of a negative relationship between human development and the capacity challenges to meet SDG 6.3.2 monitoring requirements. This negative relationship increases along the course of the monitoring process, from defining the enabling environment, choosing parameters for the collection of field data, to the analytics and analysis of five commonly used parameters (DO, EC, pH, TP and TN). Our assessment can be used to help practitioners improve technical capacity development activities and to identify and target investment in capacity development for monitoring

Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae

The protocadherins Fat4 and Dchs1 act as a receptor-ligand pair to regulate many developmental processes in mice and humans, including development of the vertebrae. Based on conservation of function between Drosophila and mammals, Fat4-Dchs1 signalling has been proposed to regulate planar cell polarity (PCP) and activity of the Hippo effectors Yap and Taz, which regulate cell proliferation, survival and differentiation. There is strong evidence for Fat regulation of PCP in mammals but the link with the Hippo pathway is unclear. In Fat4(−/−) and Dchs1(−/−) mice, many vertebrae are split along the midline and fused across the anterior-posterior axis, suggesting that these defects might arise due to altered cell polarity and/or changes in cell proliferation/differentiation. We show that the somite and sclerotome are specified appropriately, the transcriptional network that drives early chondrogenesis is intact, and that cell polarity within the sclerotome is unperturbed. We find that the key defect in Fat4 and Dchs1 mutant mice is decreased proliferation in the early sclerotome. This results in fewer chondrogenic cells within the developing vertebral body, which fail to condense appropriately along the midline. Analysis of Fat4;Yap and Fat4;Taz double mutants, and expression of their transcriptional target Ctgf, indicates that Fat4-Dchs1 regulates vertebral development independently of Yap and Taz. Thus, we have identified a new pathway crucial for the development of the vertebrae and our data indicate that novel mechanisms of Fat4-Dchs1 signalling have evolved to control cell proliferation within the developing vertebrae

Age Differences in the Associations Between Incarceration and Subsequent Substance Use, Sexual Risk-Taking, and Incident STI Among Black Sexual Minority Men and Black Transgender Women in the HIV Prevention Trials 061 Cohort

Incarceration can lead to different risk behaviors often due to increased distress and disruption of social networks. It is not well known, however, how these associations may differ by age. In this study, we measure age differences in longitudinal associations between incarceration and substance use, sex risk, and sexually transmitted infection (STI) among Black sexual minority men and Black transgender women (BSMM/BTW). We recruited BSMM/BTW from 2009 to 2011 that were part of the HIV Prevention Trials Network 061 study. We compared those less than 30 years old (n = 375) to those 30 years old or greater (n = 794) examining substance use, sex risk, and STI infection stratified by age. Logistic regression with inverse probability weighting was used for the statistical analysis. Approximately 59% of the sample reported incarceration history. In adjusted analysis, incarceration was more strongly associated with alcohol use and stimulant use among older individuals as was sexual risk behaviors including buying and selling sex. Concurrent partnerships were associated with the younger age groups. STI incidence was associated with younger individuals while associations with HIV infection were similar for the two age groups. Understanding differences in substance use and STI risk among age cohorts is imperative to the design and implementation of re-entry programs. Younger BSMM/BTW participating in re-entry support programs may benefit in particular from HIV/STI prevention and care efforts, while post-release substance abuse treatment and harm reduction programs should target older individuals with continued substance abuse