Nuclear Export of the Oncoprotein v-ErbA Is Mediated by Acquisition of a Viral Nuclear Export Sequence

v-ErbA, an oncogenic derivative of the thyroid hormone receptor α (TRα) carried by the avian erythroblastosis virus, contains several alterations including fusion of a portion of avian erythroblastosis virus Gag to its N terminus, N- and C-terminal deletions, and 13 amino acid substitutions. Nuclear export of v-ErbA occurs through a CRM1-mediated pathway. In contrast, nuclear export of TRα and another isoform, TRβ, is CRM1-independent. To determine which amino acid changes in v-ErbA confer CRM1-dependent nuclear export, we expressed a panel of green and yellow fluorescent protein-tagged mutant and chimeric proteins in mammalian cells. The sensitivity of subcellular trafficking of these mutants to leptomycin B (LMB), a specific inhibitor of CRM1, was assessed by fluorescence microscopy. Our data showed that a nuclear export sequence resides within a 70-amino acid domain in the C-terminal portion of the p10 region of Gag, and in vitro binding assays demonstrated that Gag interacts directly with CRM1. However, a panel of ligand-binding domain mutants of v-ErbA lacking the Gag sequence exhibited greater nuclear localization in the presence of LMB, suggesting that the various amino acid substitutions/deletions may cause a conformation shift, unmasking an additional CRM1-dependent nuclear export sequence. In contrast, the altered DNA-binding domain of the oncoprotein did not contribute to CRM1-dependent nuclear export. Heterokaryon experiments revealed that v-ErbA did not undergo nucleocytoplasmic shuttling when the CRM1 export pathway was blocked by LMB treatment, suggesting that the ability to follow the export pathway used by TRα has been lost by the oncoprotein during its evolution. Our findings thus point to the intriguing possibility that acquisition of altered nuclear export capabilities contributes to the oncogenic properties of v-ErbA

The weed community affects yield and quality of soybean (Glycine max (L.) Merr.)

The relationship between the weed community and soybean (Glycine max (L.) Merr.) seed yield and quality was assessed in two soybean experiments in Illinois, USA. One field was sown with different proportions of target weeds (Ambrosia trifida L., Amaranthus rudis J. Sauer, Setaria faberi F. Herrm), and the other was naturally infested with these and other weeds. The composition of the weed communities in both fields were compared to final yield and quality (% protein, oil, and water) of the crop using NMDS ordination. Biomass and canopy cover, and seed quality (% protein, relative water content, seed weight) of the crop, were related to the multivariate structure of the weed community in both experiments. Lower quality soybeans were harvested from plots dominated by the target weeds and a suite of subordinate volunteers. Analysis restricted to the volunteer weed community was also significantly related to seed protein and seed weight. Similar results from the two experiments lend generality to the findings and indicate that soybean producers need to manage the composition of the weed community

Organic electrode coatings for next-generation neural interfaces

Traditional neuronal interfaces utilize metallic electrodes which in recent years have reached a plateau in terms of the ability to provide safe stimulation at high resolution or rather with high densities of microelectrodes with improved spatial selectivity. To achieve higher resolution it has become clear that reducing the size of electrodes is required to enable higher electrode counts from the implant device. The limitations of interfacing electrodes including low charge injection limits, mechanical mismatch and foreign body response can be addressed through the use of organic electrode coatings which typically provide a softer, more roughened surface to enable both improved charge transfer and lower mechanical mismatch with neural tissue. Coating electrodes with conductive polymers or carbon nanotubes offers a substantial increase in charge transfer area compared to conventional platinum electrodes. These organic conductors provide safe electrical stimulation of tissue while avoiding undesirable chemical reactions and cell damage. However, the mechanical properties of conductive polymers are not ideal, as they are quite brittle. Hydrogel polymers present a versatile coating option for electrodes as they can be chemically modified to provide a soft and conductive scaffold. However, the in vivo chronic inflammatory response of these conductive hydrogels remains unknown. A more recent approach proposes tissue engineering the electrode interface through the use of encapsulated neurons within hydrogel coatings. This approach may provide a method for activating tissue at the cellular scale, however, several technological challenges must be addressed to demonstrate feasibility of this innovative idea. The review focuses on the various organic coatings which have been investigated to improve neural interface electrodes

Predicting Quantitative Genetic Interactions by Means of Sequential Matrix Approximation

Despite the emerging experimental techniques for perturbing multiple genes and measuring their quantitative phenotypic effects, genetic interactions have remained extremely difficult to predict on a large scale. Using a recent high-resolution screen of genetic interactions in yeast as a case study, we investigated whether the extraction of pertinent information encoded in the quantitative phenotypic measurements could be improved by computational means. By taking advantage of the observation that most gene pairs in the genetic interaction screens have no significant interactions with each other, we developed a sequential approximation procedure which ranks the mutation pairs in order of evidence for a genetic interaction. The sequential approximations can efficiently remove background variation in the double-mutation screens and give increasingly accurate estimates of the single-mutant fitness measurements. Interestingly, these estimates not only provide predictions for genetic interactions which are consistent with those obtained using the measured fitness, but they can even significantly improve the accuracy with which one can distinguish functionally-related gene pairs from the non-interacting pairs. The computational approach, in general, enables an efficient exploration and classification of genetic interactions in other studies and systems as well

The Sediment Green-Blue Color Ratio as a Proxy for Biogenic Silica Productivity Along the Chilean Margin

Sediment cores recently collected from the Chilean Margin during D/V JOIDES Resolution Expedition 379T (JR100) document variability in shipboard-generated records of the green/blue (G/B) ratio. These changes show a strong coherence with benthic foraminiferal δ18O, Antarctic ice core records, and sediment lithology (e.g., higher diatom abundances in greener sediment intervals), suggesting a climate-related control on the G/B. Here, we test the utility of G/B as a proxy for diatom productivity at Sites J1002 and J1007 by calibrating G/B to measured biogenic opal. Strong exponential correlations between measured opal% and the G/B were found at both sites. We use the empirical regressions to generate high-resolution records of opal contents (opal%) on the Chilean Margin. Higher productivity tends to result in more reducing sedimentary conditions. Redox-sensitive sedimentary U/Th generally co-varies with the reconstructed opal% at both sites, supporting the association between sediment color, sedimentary U/Th, and productivity. Lastly, we calculated opal mass accumulation rate (MAR) at Site J1007 over the last ∼150,000 years. The G/B-derived opal MAR record from Site J1007 largely tracks existing records derived from traditional wet-alkaline digestion from the south and eastern equatorial Pacific (EEP) Ocean, with a common opal flux peak at ∼50 ka suggesting that increased diatom productivity in the EEP was likely driven by enhanced nutrient supply from the Southern Ocean rather than dust inputs as previously suggested. Collectively, our results identify the G/B ratio as a useful tool with the potential to generate reliable, high-resolution paleoceanographic records that circumvent the traditionally laborious methodology.publishedVersio

Brain connectivity changes in autosomal recessive Parkinson Disease: a model for the sporadic form

Biallelic genetic mutations in the Park2 and PINK1 genes are frequent causes of autosomal recessive PD. Carriers of single heterozygous mutations may manifest subtle signs of disease, thus providing a unique model of preclinical PD. One emerging hypothesis suggests that non-motor symptom of PD, such as cognitive impairment may be due to a distributed functional disruption of various neuronal circuits. Using resting-state functional MRI (RS-fMRI), we tested the hypothesis that abnormal connectivity within and between brain networks may account for the patients' cognitive status. Eight homozygous and 12 heterozygous carriers of either PINK1 or Park2 mutation and 22 healthy controls underwent RS-fMRI and cognitive assessment. RS-fMRI data underwent independent component analysis to identify five networks of interest: default-mode network, salience network, executive network, right and left fronto-parietal networks. Functional connectivity within and between each network was assessed and compared between groups. All mutation carriers were cognitively impaired, with the homozygous group reporting a more prominent impairment in visuo-spatial working memory. Changes in functional connectivity were evident within all networks between homozygous carriers and controls. Also heterozygotes reported areas of reduced connectivity when compared to controls within two networks. Additionally, increased inter-network connectivity was observed in both groups of mutation carriers, which correlated with their spatial working memory performance, and could thus be interpreted as compensatory. We conclude that both homozygous and heterozygous carriers exhibit pathophysiological changes unveiled by RS-fMRI, which can account for the presence/severity of cognitive symptom

Controlled Experiments of Hillslope Coevolution at the Biosphere 2 Landscape Evolution Observatory: Toward Prediction of Coupled Hydrological, Biogeochemical, and Ecological Change

Understanding the process interactions and feedbacks among water, porous geological media, microbes, and vascular plants is crucial for improving predictions of the response of Earth’s critical zone to future climatic conditions. However, the integrated coevolution of landscapes under change is notoriously difficult to investigate. Laboratory studies are limited in spatial and temporal scale, while field studies lack observational density and control. To bridge the gap between controlled laboratory and uncontrollable field studies, the University of Arizona built a macrocosm experiment of unprecedented scale: the Landscape Evolution Observatory (LEO). LEO comprises three replicated, heavily instrumented, hillslope-scale model landscapes within the environmentally controlled Biosphere 2 facility. The model landscapes were designed to initially be simple and purely abiotic, enabling scientists to observe each step in the landscapes’ evolution as they undergo physical, chemical, and biological changes over many years. This chapter describes the model systems and associated research facilities and illustrates how LEO allows for tracking of multiscale matter and energy fluxes at a level of detail impossible in field experiments. Initial sensor, sampler, and soil coring data are already providing insights into the tight linkages between water flow, weathering, and microbial community development. These interacting processes are anticipated to drive the model systems to increasingly complex states and will be impacted by the introduction of vascular plants and changes in climatic regimes over the years to come. By intensively monitoring the evolutionary trajectory, integrating data with mathematical models, and fostering community-wide collaborations, we envision that emergent landscape structures and functions can be linked, and significant progress can be made toward predicting the coupled hydro-biogeochemical and ecological responses to global change

Comparative determination of HIV-1 co-receptor tropism by Enhanced Sensitivity Trofile, gp120 V3-loop RNA and DNA genotyping

BACKGROUND: Trofile is the prospectively validated HIV-1 tropism assay. Its use is limited by high costs, long turn-around time, and inability to test patients with very low or undetectable viremia. We aimed at assessing the efficiency of population genotypic assays based on gp120 V3-loop sequencing for the determination of tropism in plasma viral RNA and in whole-blood viral DNA. Contemporary and follow-up plasma and whole-blood samples from patients undergoing tropism testing via the enhanced sensitivity Trofile (ESTA) were collected. Clinical and clonal geno2pheno[coreceptor] (G2P) models at 10% and at optimised 5.7% false positive rate cutoff were evaluated using viral DNA and RNA samples, compared against each other and ESTA, using Cohen's kappa, phylogenetic analysis, and area under the receiver operating characteristic (AUROC). RESULTS: Both clinical and clonal G2P (with different false positive rates) showed good performances in predicting the ESTA outcome (for V3 RNA-based clinical G2P at 10% false positive rate AUROC = 0.83, sensitivity = 90%, specificity = 75%). The rate of agreement between DNA- and RNA-based clinical G2P was fair (kappa = 0.74, p < 0.0001), and DNA-based clinical G2P accurately predicted the plasma ESTA (AUROC = 0.86). Significant differences in the viral populations were detected when comparing inter/intra patient diversity of viral DNA with RNA sequences. CONCLUSIONS: Plasma HIV RNA or whole-blood HIV DNA V3-loop sequencing interpreted with clinical G2P is cheap and can be a good surrogate for ESTA. Although there may be differences among viral RNA and DNA populations in the same host, DNA-based G2P may be used as an indication of viral tropism in patients with undetectable plasma viremia

Deep submarine infiltration of altered geothermal groundwater on the south Chilean Margin

Submarine groundwater discharge is increasingly recognized as an important component of the oceanic geochemical budget, but knowledge of the distribution of this phenomenon is limited. To date, reports of meteoric inputs to marine sediments are typically limited to shallow shelf and coastal environments, whereas contributions of freshwater along deeper sections of tectonically active margins have generally been attributed to silicate diagenesis, mineral dehydration, or methane hydrate dissociation. Here, using geochemical fingerprinting of pore water data from Site J1003 recovered from the Chilean Margin during D/V JOIDES Resolution Expedition 379 T, we show that substantial offshore freshening reflects deep and focused contributions of meteorically modified geothermal groundwater, which is likely sourced from a reservoir ~2.8 km deep in the Aysén region of Patagonia and infiltrated marine sediments during or shortly after the last glacial period. Emplacement of fossil groundwaters reflects an apparently ubiquitous phenomenon in margin sediments globally, but our results now identify an unappreciated locus of deep submarine groundwater discharge along active margins with potential implications for coastal biogeochemical processes and tectonic instability.publishedVersio

A genomic storm in critically injured humans

Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes