Folic acid induces cell type-specific changes in the transcriptome of breast cancer cell lines: a proof-of-concept study

The effect of folic acid (FA) on breast cancer (BC) risk is uncertain. We hypothesised that this uncertainty may be due, in part, to differential effects of FA between BC cells with different phenotypes. To test this we investigated the effect of treatment with FA concentrations within the range of unmetabolised FA reported in humans on the expression of the transcriptome of non-transformed (MCF10A) and cancerous (MCF7 and Hs578T) BC cells. The total number of transcripts altered was MCF10A 75 (70 up-regulated), MCF7 24 (14 up-regulated) and Hs578T 328 (156 up-regulated). Only the cancer-associated gene TAGLN was altered by FA in all three cell lines. In MCF10A and Hs578T cells, FA treatment decreased pathways associated with apoptosis, cell death and senescence, but increased those associated with cell proliferation. The folate transporters SLC19A1, SLC46A1 and FOLR1 were differentially expressed between cell lines tested. However, the level of expression was not altered by FA treatment. These findings suggest that physiological concentrations of FA can induce cell type-specific changes in gene regulation in a manner that is consistent with proliferative phenotype. This has implications for understanding the role of FA in BC risk. In addition, these findings support the suggestion the differences in gene expression induced by FA may involve differential activities of folate transporters. Together these findings indicate the need for further studies of the effect of FA on BC

Simulating Physical Phenomena by Quantum Networks

Physical systems, characterized by an ensemble of interacting elementary constituents, can be represented and studied by different algebras of observables or operators. For example, a fully polarized electronic system can be investigated by means of the algebra generated by the usual fermionic creation and annihilation operators, or by using the algebra of Pauli (spin-1/2) operators. The correspondence between the two algebras is given by the Jordan-Wigner isomorphism. As we previously noted similar one-to-one mappings enable one to represent any physical system in a quantum computer. In this paper we evolve and exploit this fundamental concept in quantum information processing to simulate generic physical phenomena by quantum networks. We give quantum circuits useful for the efficient evaluation of the physical properties (e.g, spectrum of observables or relevant correlation functions) of an arbitrary system with Hamiltonian $H$.Comment: 44 pages, 15 psfigur

Environmental adaptation in stomatal size independent of the effects of genome size

Cell sizes are linked across multiple tissues, including stomata, and this variation is closely correlated with genome size. These associations raise the question of whether generic changes in cell size cause suboptimal changes in stomata, requiring subsequent evolution under selection for stomatal size. We tested the relationships among guard cell length, genome size and vegetation type using phylogenetically independent analyses on 67 species of the ecologically and structurally diverse family, Proteaceae. We also compared how genome and stomatal sizes varied at ancient (among genera) and more recent (within genus) levels. The observed 60-fold range in genome size in Proteaceae largely reflected the mean chromosome size. Compared with variation among genera, genome size varied much less within genera (< 6% of total variance) than stomatal size, implying evolution in stomatal size subsequent to changes in genome size. Open vegetation and closed forest had significantly different relationships between stomatal and genome sizes. Ancient changes in genome size clearly influenced stomatal size in Proteaceae, but adaptation to habitat strongly modified the genome-stomatal size relationship. Direct adaptation to the environment in stomatal size argues that new proxies for past concentrations of atmospheric CO2 that incorporate stomatal size are superior to older models based solely on stomatal frequency.Gregory J. Jordan, Raymond J. Carpenter, Anthony Koutoulis, Aina Price and Timothy J. Brodrib

Dissecting a complex chemical stress: chemogenomic profiling of plant hydrolysates.

The efficient production of biofuels from cellulosic feedstocks will require the efficient fermentation of the sugars in hydrolyzed plant material. Unfortunately, plant hydrolysates also contain many compounds that inhibit microbial growth and fermentation. We used DNA-barcoded mutant libraries to identify genes that are important for hydrolysate tolerance in both Zymomonas mobilis (44 genes) and Saccharomyces cerevisiae (99 genes). Overexpression of a Z. mobilis tolerance gene of unknown function (ZMO1875) improved its specific ethanol productivity 2.4-fold in the presence of miscanthus hydrolysate. However, a mixture of 37 hydrolysate-derived inhibitors was not sufficient to explain the fitness profile of plant hydrolysate. To deconstruct the fitness profile of hydrolysate, we profiled the 37 inhibitors against a library of Z. mobilis mutants and we modeled fitness in hydrolysate as a mixture of fitness in its components. By examining outliers in this model, we identified methylglyoxal as a previously unknown component of hydrolysate. Our work provides a general strategy to dissect how microbes respond to a complex chemical stress and should enable further engineering of hydrolysate tolerance

Latent HIV in primary T lymphocytes is unresponsive to histone deacetylase inhibitors

Recently, there is considerable interest in the field of anti-HIV therapy to identify and develop chromatin-modifying histone deacetylase (HDAC) inhibitors that can effectively reactivate latent HIV in patients. The hope is that this would help eliminate cells harboring latent HIV and achieve an eventual cure of the virus. However, how effectively these drugs can stimulate latent HIVs in quiescent primary CD4 T cells, despite their relevant potencies demonstrated in cell line models of HIV latency, is not clear. Here, we show that the HDAC inhibitors valproic acid (VPA) and trichostatin A (TSA) are unable to reactivate HIV in latently infected primary CD4 T cells generated in the H80 co-culture system. This raises a concern that the drugs inhibiting HDAC function alone might not be sufficient for stimulating latent HIV in resting CD4 T cells in patients and not achieve any anticipated reduction in the pool of latent reservoirs

Mechanisms, predictors, and evolution of severe peri-device leaks with two different left atrial appendage occluders.

AIMS Incomplete left atrial appendage occlusion (LAAO) due to peri-device leak (PDL) is a limitation of the therapy. The Amulet IDE trial is the largest randomized head-to-head trial comparing the Amulet and Watchman 2.5 LAAO devices with fundamentally different designs. The predictors and mechanistic factors impacting differences in PDLs within the Amulet IDE trial are assessed in the current analysis. METHODS AND RESULTS An independent core lab analysed all images for the presence or absence of severe PDL (>5 mm). The incidence, mechanistic factors, predictors using propensity score-matched controls, and evolution of severe PDLs through 18 months were assessed. Of the 1878 patients randomized in the trial, the Amulet occluder had significantly fewer severe PDLs than the Watchman device at 45 days (1.1 vs. 3.2%, P < 0.001) and 12 months (0.1 vs. 1.1%, P < 0.001). Off-axis deployment or missed lobes were leading mechanistic PDL factors in each device group. Larger left atrial appendage (LAA) dimensions including orifice diameter, landing zone diameter, and depth predicted severe PDL with the Watchman device, with no significant anatomical limitations noted with the Amulet occluder. Procedural and device implant predictors were found with the Amulet occluder attributed to the learning curve with the device. A majority of Watchman device severe PDLs did not resolve over time through 18 months. CONCLUSION The dual-occlusive Amplatzer Amulet LAA occluder provided improved LAA closure compared with the Watchman 2.5 device. Predictors and temporal observations of severe PDLs were identified in the Amulet IDE trial. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov Unique identifier NCT02879448

An Updated Dust-to-Star Geometry: Dust Attenuation Does Not Depend on Inclination in 1.3≤z≤2.61.3\leq z\leq 2.6 Star-Forming Galaxies from MOSDEF

We investigate dust attenuation and its dependence on viewing angle for 308 star-forming galaxies at $1.3\leq z\leq2.6$ from the MOSFIRE Deep Evolution Field (MOSDEF) survey. We divide galaxies with a detected H$\alpha$ emission line and coverage of H$\beta$ into eight groups by stellar mass, star formation rate (SFR), and inclination (i.e., axis ratio), then stack their spectra. From each stack, we measure Balmer decrement and gas-phase metallicity, then we compute median \AV and UV continuum spectral slope ($\beta$). First, we find that none of the dust properties (Balmer decrement, \AV, $\beta$) vary with axis ratio. Second, both stellar and nebular attenuation increase with increasing galaxy mass, showing little residual dependence on SFR or metallicity. Third, nebular emission is more attenuated than stellar emission, and this difference grows even larger at higher galaxy masses and SFRs. Based on these results, we propose a three-component dust model where attenuation predominantly occurs in star-forming regions and large, dusty star-forming clumps, with minimal attenuation in the diffuse ISM. In this model, nebular attenuation primarily originates in clumps, while stellar attenuation is dominated by star-forming regions. Clumps become larger and more common with increasing galaxy mass, creating the above mass trends. Finally, we argue that a fixed metal yield naturally leads to mass regulating dust attenuation. Infall of low-metallicity gas increases SFR and lowers metallicity, but leaves dust column density mostly unchanged. We quantify this idea using the Kennicutt-Schmidt and fundamental metallicity relations, showing that galaxy mass is indeed the primary driver of dust attenuation.Comment: 19 pages, 13 figures, accepted for publication in Ap

DendroBlast: approximate phylogenetic trees in the absence of multiple sequence alignments

The rapidly growing availability of genome information has created considerable demand for both fast and accurate phylogenetic inference algorithms. We present a novel method called DendroBLAST for reconstructing phylogenetic dendrograms/trees from protein sequences using BLAST. This method differs from other methods by incorporating a simple model of sequence evolution to test the effect of introducing sequence changes on the reliability of the bipartitions in the inferred tree. Using realistic simulated sequence data we demonstrate that this method produces phylogenetic trees that are more accurate than other commonly-used distance based methods though not as accurate as maximum likelihood methods from good quality multiple sequence alignments. In addition to tests on simulated data, we use DendroBLAST to generate input trees for a supertree reconstruction of the phylogeny of the Archaea. This independent analysis produces an approximate phylogeny of the Archaea that has both high precision and recall when compared to previously published analysis of the same dataset using conventional methods. Taken together these results demonstrate that approximate phylogenetic trees can be produced in the absence of multiple sequence alignments, and we propose that these trees will provide a platform for improving and informing downstream bioinformatic analysis. A web implementation of the DendroBLAST method is freely available for use at http://www.dendroblast.com/