Aberrant Glycosylation in Cancer: A Novel Molecular Mechanism Controlling Metastasis

Glycosylation alterations are involved in several steps of human cancer pathogenesis. In this issue of Cancer Cell, Agrawal et al. identified the glycosyltransferase FUT8 as a previously unrecognized mediator of melanoma metastasis, establishing core fucosylation as a potential therapeutic target for prevention and treatment of metastatic tumors.The authors acknowledge funding by FEDER, COMPETE and FCT: POCI-01-0145-FEDER-007274 (UID/BIM/04293/2013), POCI-01-0145-FEDER-016585 (PTDC/BBB-EBI/0567/2014), NORTE 2020 (NORTE-01-0145-FEDER-000029), and EU 7th Framework Programme ITN 316929

Fluorometric Liposome Screen for Inhibitors of a Physiologically Important Bacterial Ion Channel

The bacterial K+ homeostasis machinery is widely conserved across bacterial species, and different from that in animals. Dysfunction in components of the machinery has an impact on intracellular turgor, membrane potential, adaptation to changes in both extracellular pH and osmolarity, and in virulence. Using a fluorescence-based liposome flux assay, we have performed a high-throughput screen to identify novel inhibitors of the KtrAB ion channel complex from Bacillus subtilis, a component of the K+ homeostasis machinery that is also present in many bacterial pathogens. The screen identified 41 compounds that inhibited K+ flux and that clustered into eight chemical groups. Many of the identified inhibitors were found to target KtrAB with an in vitro potency in the low µM range. We investigated the mechanisms of inhibition and found that most molecules affected either the membrane component of the channel, KtrB alone or the full KtrAB complex without a preference for the functional conformation of the channel, thus broadening their inhibitory action. A urea derivative molecule that inhibited the membrane component of KtrAB affected cell viability in conditions in which KtrAB activity is essential. With this proof-of-concept study, we demonstrate that targeting components of the K+ homeostasis machinery has the potential as a new antibacterial strategy and that the fluorescence-based flux assay is a robust tool for screening chemical libraries.This work was supported by FEDER funds through COMPETE 2020-POCI, Portugal 2020, and FCT – Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior: POCI-01-0145-FEDER-029863 (PTDC/BIA-BQM/29863/2017), and by “Fundação Luso-Americana para o Desenvolvimento” FLAD Life Science 2020 awarded to JM-C. We acknowledge FCT fellowship SFRH/BPD/105672/2015 and contract DL 57/2016/CP1355/CT0026 awarded to AF, fellowship SFRH/BPD/107785/2015 to AP, and fellowship SFRH/BD/123761/2016 to CT-D

Landslides on Ceres: Diversity and Geologic Context.

Landslides are among the most widespread geologic features on Ceres. Using data from Dawn's Framing Camera, landslides were previously classified based upon geomorphologic characteristics into one of three archetypal categories, Type 1(T1), Type 2 (T2), and Type 3 (T3). Due to their geologic context, variation in age, and physical characteristics, most landslides on Ceres are, however, intermediate in their morphology and physical properties between the archetypes of each landslide class. Here we describe the varied morphology of individual intermediate landslides, identify geologic controls that contribute to this variation, and provide first-order quantification of the physical properties of the continuum of Ceres's surface flows. These intermediate flows appear in varied settings and show a range of characteristics, including those found at contacts between craters, those having multiple trunks or lobes; showing characteristics of both T2 and T3 landslides; material slumping on crater rims; very small, ejecta-like flows; and those appearing inside of catenae. We suggest that while their morphologies can vary, the distribution and mechanical properties of intermediate landslides do not differ significantly from that of archetypal landslides, confirming a link between landslides and subsurface ice. We also find that most intermediate landslides are similar to Type 2 landslides and formed by shallow failure. Clusters of these features suggest ice enhancement near Juling, Kupalo and Urvara craters. Since the majority of Ceres's landslides fall in the intermediate landslide category, placing their attributes in context contributes to a better understanding of Ceres's shallow subsurface and the nature of ground ice

Effects of temperature and ocean acidification on shell characteristics of Argopecten purpuratus: implications for scallop aquaculture in an upwelling-influenced area

Coastal upwelling regions already constitute hot spots of ocean acidification as naturally acidified waters are brought to the surface. This effect could be exacerbated by ocean acidification and warming, both caused by rising concentrations of atmospheric CO2. Along the Chilean coast, upwelling supports highly productive fisheries and aquaculture activities. However, during recent years, there has been a documented decline in the national production of the native scallop Argopecten purpuratus. We assessed the combined effects of temperature and pCO2-driven ocean acidification on the growth rates and shell characteristics of this species farmed under the natural influence of upwelling waters occurring in northern Chile (30° S, Tongoy Bay). The experimental scenario representing current conditions (14°C, pH ~8.0) were typical of natural values recorded in Tongoy Bay, whilst conditions representing the low pH scenario were typical of an adjacent upwelling area (pH ~7.6). Shell thickness, weight, and biomass were reduced under low pH (pH ~7.7)and increased temperature (18°C) conditions. At ambient temperature (14°C) and low pH, scallops showed increased shell dissolution and low growth rates. However, elevated temperatures ameliorated the impacts of low pH, as evidenced by growth rates in both pH treatments at the higher temperature treatment that were not significantly different from the control treatment. The impact of low pH at current temperature on scallop growth suggests that the upwelling could increase the time required for scallops to reach marketable size. Mortality of farmed scallops is discussed in relation to our observations of multiple environmental stressors in this upwelling-influenced area

Species-specific responses to ocean acidification should account for local adaptation and adaptive plasticity

Global stressors, such as ocean acidification, constitute a rapidly emerging and significant problem for marine organisms, ecosystem functioning and services. The coastal ecosystems of the Humboldt Current System (HCS) off Chile harbour a broad physical–chemical latitudinal and temporal gradient with considerable patchiness in local oceanographic conditions. This heterogeneity may, in turn, modulate the specific tolerances of organisms to climate stress in species with populations distributed along this environmental gradient. Negative response ratios are observed in species models (mussels, gastropods and planktonic copepods) exposed to changes in the partial pressure of CO2 (pCO2) far from the average and extreme pCO2 levels experienced in their native habitats. This variability in response between populations reveals the potential role of local adaptation and/or adaptive phenotypic plasticity in increasing resilience of species to environmental change. The growing use of standard ocean acidification scenarios and treatment levels in experimental protocols brings with it a danger that inter-population differences are confounded by the varying environmental conditions naturally experienced by different populations. Here, we propose the use of a simple index taking into account the natural pCO2 variability, for a better interpretation of the potential consequences of ocean acidification on species inhabiting variable coastal ecosystems. Using scenarios that take into account the natural variability will allow understanding of the limits to plasticity across organismal traits, populations and species

Ginger Essential Oil Ameliorates Cisplatin-Induced Nephrotoxicity in Mice

Purpose: To investigate the effect of ginger essential oil (GEO) in an experimental model of cisplatininduced nephrotoxicity.Methods: Male mice were divided into treatment six groups (n = 7), namely: Groups I (saline), II and III (cisplatin, 10 mg/kg, i.p.) euthanized in 3th and 6th days, respectively, and IV, V and IV (GEO, 100, 200 and 400 mg/kg/day, respectively, by gavage 3, 4, 5 and 6 days after cisplatin injection). Creatinine levels and protein/creatinine ratio were determined in plasma and urine, respectively. Bone morphogenic protein (BMP-7) and tumor necrosis factor (TNF-α) levels of kidney tissues were determined while mRNA expression levels were obtained using real-time polymerase chain reaction.Results: GEO treatment reduced significantly creatinine levels to 0.53 ± 0.02; 0.48 ± 0.008 and 0.46 ± 0.02 at 100, 200 and 400 mg/kg, respectively, compared with control (0.70 ± 0.01) [p<0.05] but increased protein : creatinine ratio to 0.21 ± 0.01, 0.22 ± 0.01, 0.24 ± 0.02 compared with control (0.06 ± 0.008) [p<0.05]. Pro-inflammatory TNF-α mRNA expression was decreased to 1.46 ± 0.21, 1.39 ± 0.19 and 1.36 ± 0.09, at GEO doses of 100, 200 and 400 mg/kg, respectively, while anti-fibrotic BMP-7 mRNA expression increased to 2.05 ± 0.26 and 2.44 ± 0.42 at doses of 200 and 400 mg/kg, respectively, compared with control (0.59 ± 0.39, p < 0.05).Conclusion: GEO treatment attenuates cisplatin-induced nephrotoxicity, in part, by modulating some inflammatory cytokines.Keywords: Zingiber officinale, Ginger, Roscoe, Essential oil, Nephrotoxicity, Cisplati

Ocean Acidification Disrupts Prey Responses to Predator Cues but Not Net Prey Shell Growth in Concholepas concholepas (loco)

Background Most research on Ocean Acidification (OA) has largely focused on the process of calcification and the physiological trade-offs employed by calcifying organisms to support the building of calcium carbonate structures. However, there is growing evidence that OA can also impact upon other key biological processes such as survival, growth and behaviour. On wave-swept rocky shores the ability of gastropods to self-right after dislodgement, and rapidly return to normal orientation, reduces the risk of predation. Methodology/Principal Findings The impacts of OA on this self-righting behaviour and other important parameters such as growth, survival, shell dissolution and shell deposition in Concholepas concholepas (loco) were investigated under contrasting pCO2 levels. Although no impacts of OA on either growth or net shell calcification were found, the results did show that OA can significantly affect self-righting behaviour during the early ontogeny of this species with significantly faster righting times recorded for individuals of C. concholepas reared under increased average pCO2 concentrations (± SE) (716±12 and 1036±14 µatm CO2) compared to those reared at concentrations equivalent to those presently found in the surface ocean (388±8 µatm CO2). When loco were also exposed to the predatory crab Acanthocyclus hassleri, righting times were again increased by exposure to elevated CO2, although self-righting times were generally twice as fast as those observed in the absence of the crab. Conclusions and Significance These results suggest that self-righting in the early ontogeny of C. concholepas will be positively affected by pCO2 levels expected by the end of the 21st century and beginning of the next one. However, as the rate of self-righting is an adaptive trait evolved to reduce lethal predatory attacks, our result also suggest that OA may disrupt prey responses to predators in nature

In vitro mutation artifacts after formalin fixation and error prone translesion synthesis during PCR

BACKGROUND: Clinical specimens are routinely fixed in 10% buffered formalin and paraffin embedded. Although DNA is commonly extracted from fixed tissues and amplified by PCR, the effects of formalin fixation are relatively unknown. Formalin fixation is known to impair PCR, presumably through damage that blocks polymerase elongation, but an insidious possibility is error prone translesion synthesis across sites of damage, producing in vitro artifactual mutations during PCR. METHODS: To better understand the consequences of fixation, DNA specimens extracted from fresh or fixed tissues were amplified with Taq DNA polymerase, and their PCR products were cloned and sequenced. RESULTS: Significantly more (3- to 4-fold) mutations were observed with fixed DNA specimens. The majority of mutations were transitions, predominantly at A:T base pairs, randomly distributed along the template. CONCLUSIONS: Formalin fixation appears to cause random base damage, which can be bridged during PCR by Taq DNA polymerase through error prone translesion synthesis. Fixed DNA is a damaged but "readable" template

HIV Types, Groups, Subtypes and Recombinant Forms: Errors in Replication, Selection Pressure and Quasispecies

HIV-1 is a chimpanzee virus which was transmitted to humans by several zoonotic events resulting in infection with HIV-1 groups M P, and in parallel transmission events from sooty mangabey monkey viruses leading to infections with HIV-2 groups A H. Both viruses have circulated in the human population for about 80 years. In the infected patient, HIV mutates, and by elimination of some of the viruses by the action of the immune system individual quasispecies are formed. Along with the selection of the fittest viruses, mutation and recombination after superinfection with HIV from different groups or subtypes have resulted in the diversity of their patterns of geographic distribution. Despite the high variability observed, some essential parts of the HIV genome are highly conserved. Viral diversity is further facilitated in some parts of the HIV genome by drug selection pressure and may also be enhanced by different genetic factors, including HLA in patients from different regions of the world. Viral and human genetic factors influence pathogenesis. Viral genetic factors are proteins such as Tat, Vif and Rev. Human genetic factors associated with a better clinical outcome are proteins such as APOBEC, langerin, tetherin and chemokine receptor 5 (CCR5) and HLA B27, B57, DRB1{*}1303, KIR and PARD3B. Copyright (C) 2012 S. Karger AG, Base