Dark/Visible Parallel Universes and Big Bang Nucleosynthesis

We develop a model for visible matter-dark matter interaction based on the exchange of a massive gray boson called herein the Mulato. Our model hinges on the assumption that all known particles in the visible matter have their counterparts in the dark matter. We postulate six families of particles five of which are dark. This leads to the unavoidable postulation of six parallel worlds, the visible one and five invisible worlds. A close study of big bang nucleosynthesis (BBN), baryon asymmetries, cosmic microwave background (CMB) bounds, galaxy dynamics, together with the Standard Model assumptions, help us to set a limit on the mass and width of the new gauge boson. Modification of the statistics underlying the kinetic energy distribution of particles during the BBN is also discussed. The changes in reaction rates during the BBN due to a departure from the Debye-Hueckel electron screening model is also investigated.Comment: Invited talk at the Workshops "CompStar: the physics and astrophysics of compact stars", Tahiti, June 4-8, 2012, "New Directions in Nuclear Astrophysics", Castiglion Fiorentino, Italy, June 18-22, 2012, and "Carpathian Summer School of Physics", Sinaia, Romania, June 24 - July 7, 2012. To be published in AIP Proceeding

Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function

This work was supported by grants from the NIH (R01CA86072 to R.G.P. and R01CA72038-01 to S.A.W.F.) and The Susan Komen Breast Cancer Foundation (to R.G.P.). R.T.H. and E.J. were supported by the Medical Research Council. Y.-G.Y. is supported by grant CA26504 to E. R. Stanley. Work conducted at the Albert Einstein College of Medicine was supported by Cancer Center Core National Institutes of Health grant 5-P30-CA13330-26.The androgen receptor (AR) is a nuclear hormone receptor superfamily member that conveys both traits repression and ligand-dependent trans-activation function. Activation of the AR by dihydrotestosterone (DHT) regulates diverse physiological functions including secondary sexual differentiation in the male and the induction of apoptosis by the JNK kinase, MEKK1. The AR is posttranslationally modified on lysine residues by acetylation and sumoylation. The histone acetylases p300 and P/CAF directly acetylate the AR in vitro at a conserved KLKK motif. To determine the functional properties governed by AR acetylation, point mutations of the KLKK motif that abrogated acetylation were engineered and examined in vitro and in vivo. The AR acetylation site point mutants showed wild-type trans repression of NF-kappaS, AP-1, and Sp1 activity; wild-type sumoylation in vitro; wild-type ligand binding; and ligand-induced conformational changes. However, acetylation-deficient AR mutants were selectively defective in DHT-induced trans activation of androgen-responsive reporter genes and coactivation by SRC1, Ubc9, TIP60, and p300. The AR acetylation site mutant showed 10-fold increased binding of the N-CoR corepressor compared with the AR wild type in the presence of ligand. Furthermore, histone deacetylase 1 (HDAC1) bound the AR both in vivo and in cultured cells and HDAC1 binding to the AR was disengaged in a DHT-dependent manner. MEKK1 induced AR-dependent apoptosis in prostate cancer cells. The AR acetylation mutant was defective in MEKK1-induced apoptosis, suggesting that the conserved AR acetylation site contributes to a pathway governing prostate cancer cellular survival. As AR lysine residue mutations that abrogate acetylation correlate with enhanced binding of the N-CoR repressor in cultured cells, the conserved AR motif may directly or indirectly regulate ligand-dependent corepressor disengagement and, thereby, ligand-dependent trans activation.Publisher PDFPeer reviewe

Evolution of the Insertion-Deletion Mutation Rate Across the Tree of Life

Citation: Sung, W., Ackerman, M. S., Dillon, M. M., Platt, T. G., Fuqua, C., Cooper, V. S., & Lynch, M. (2016). Evolution of the Insertion-Deletion Mutation Rate Across the Tree of Life. G3-Genes Genomes Genetics, 6(8), 2583-2591. doi:10.1534/g3.116.030890/-/DC1Mutations are the ultimate source of variation used for evolutionary adaptation, while also being predominantly deleterious and a source of genetic disorders. Understanding the rate of insertion-deletion mutations (indels) is essential to understanding evolutionary processes, especially in coding regions, where such mutations can disrupt production of essential proteins. Using direct estimates of indel rates from 14 phylogenetically diverse eukaryotic and bacterial species, along with measures of standing variation in such species, we obtain results that imply an inverse relationship of mutation rate and effective population size. These results, which corroborate earlier observations on the base-substitution mutation rate, appear most compatible with the hypothesis that natural selection reduces mutation rates per effective genome to the point at which the power of random genetic drift (approximated by the inverse of effective population size) becomes overwhelming. Given the substantial differences in DNA metabolism pathways that give rise to these two types of mutations, this consistency of results raises the possibility that refinement of other molecular and cellular traits may be inversely related to species-specific levels of random genetic drift

Elevated Expression of MAPK Phosphatase 3 in Breast Tumors—A Mechanism of Tamoxifen Resistance

Antiestrogen resistance is a major clinical problem in the treatment of breast cancer. Altered growth factor signaling with estrogen receptor (ER) α has been shown to be associated with the development of resistance. Gene expression profiling was utilized to identify MAPK phosphatase 3 (MKP3) whose expression was correlated with response to the antiestrogen tamoxifen in both patients and in vitro derived cell line models. Overexpression of MKP3 rendered ERα-positive breast cancer cells resistant to the growth inhibitory effects of tamoxifen, and enhanced tamoxifen agonist activity in endometrial cells. MKP3 overexpression was associated with lower levels of activated ERK1,2 phosphorylation in the presence of estrogen, but that estrogen deprivation and tamoxifen treatment decreased MKP3 phosphatase activity, leading to an up-regulation of pERK1,2 MAPK, phosphoserine 118 of ERα, and cyclin D1. The MEK inhibitor PD98059 blocked tamoxifen-resistant growth. Accumulation of reactive oxygen species was observed with tamoxifen treatment of MKP3 overexpressing cells, and antioxidant treatment increased MKP3 phosphatase activity, thereby blocking resistance. Furthermore, PD98059 increased the levels of phospho-JNK in tamoxifen-treated MKP3 overexpressing cells, suggesting an interaction between MKP3 levels, activation of ERK1,2 MAPK, and JNK signaling in human breast cancer cells. MKP3 represents a novel mechanism of resistance which may be a potential biomarker for the use of ERK1,2 and/or JNK inhibitors in combination with tamoxifen treatment

RNA sequencing of cancer reveals novel splicing alterations

Breast cancer transcriptome acquires a myriad of regulation changes, and splicing is critical for the cell to “tailor-make” specific functional transcripts. We systematically revealed splicing signatures of the three most common types of breast tumors using RNA sequencing: TNBC, non-TNBC and HER2-positive breast cancer. We discovered subtype specific differentially spliced genes and splice isoforms not previously recognized in human transcriptome. Further, we showed that exon skip and intron retention are predominant splice events in breast cancer. In addition, we found that differential expression of primary transcripts and promoter switching are significantly deregulated in breast cancer compared to normal breast. We validated the presence of novel hybrid isoforms of critical molecules like CDK4, LARP1, ADD3, and PHLPP2. Our study provides the first comprehensive portrait of transcriptional and splicing signatures specific to breast cancer sub-types, as well as previously unknown transcripts that prompt the need for complete annotation of tissue and disease specific transcriptome

A pilot study comparing the metabolic profiles of elite-level athletes from different sporting disciplines

Background: The outstanding performance of an elite athlete might be associated with changes in their blood metabolic profile. The aims of this study were to compare the blood metabolic profiles between moderate- and high-power and endurance elite athletes and to identify the potential metabolic pathways underlying these differences. Methods: Metabolic profiling of serum samples from 191 elite athletes from different sports disciplines (121 high- and 70 moderate-endurance athletes, including 44 high- and 144 moderate-power athletes), who participated in national or international sports events and tested negative for doping abuse at anti-doping laboratories, was performed using non-targeted metabolomics-based mass spectroscopy combined with ultrahigh-performance liquid chromatography. Multivariate analysis was conducted using orthogonal partial least squares discriminant analysis. Differences in metabolic levels between high- and moderate-power and endurance sports were assessed by univariate linear models. Results: Out of 743 analyzed metabolites, gamma-glutamyl amino acids were significantly reduced in both high-power and high-endurance athletes compared to moderate counterparts, indicating active glutathione cycle. High-endurance athletes exhibited significant increases in the levels of several sex hormone steroids involved in testosterone and progesterone synthesis, but decreases in diacylglycerols and ecosanoids. High-power athletes had increased levels of phospholipids and xanthine metabolites compared to moderate-power counterparts. Conclusions: This pilot data provides evidence that high-power and high-endurance athletes exhibit a distinct metabolic profile that reflects steroid biosynthesis, fatty acid metabolism, oxidative stress, and energy-related metabolites. Replication studies are warranted to confirm differences in the metabolic profiles associated with athletes’ elite performance in independent data sets, aiming ultimately for deeper understanding of the underlying biochemical processes that could be utilized as biomarkers with potential therapeutic implications

Missing lithotroph identified as new planctomycete

With the increased use of chemical fertilizers in agriculture, many densely populated countries face environmental problems associated with high ammonia emissions. The process of anaerobic ammonia oxidation ('anammox') is one of the most innovative technological advances in the removal of ammonia nitrogen from waste water. This new process combines ammonia and nitrite directly into dinitrogen gas. Until now, bacteria capable of anaerobically oxidizing ammonia had never been found and were known as "lithotrophs missing from nature". Here we report the discovery of this missing lithotroph and its identification as a new, autotrophic member of the order Planctomycetales, one of the major distinct divisions of the Bacteria. The new planctomycete grows extremely slowly, dividing only once every two weeks. At present, it cannot be cultivated by conventional microbiological techniques. The identification of this bacterium as the one responsible for anaerobic oxidation of ammonia makes an important contribution to the problem of unculturability

CGM-measured glucose values have a strong correlation with C-peptide, HbA1c and IDAAC, but do poorly in predicting C-peptide levels in the two years following onset of diabetes

AIMS/HYPOTHESIS: The aim of this work was to assess the association between continuous glucose monitoring (CGM) data, HbA1c, insulin-dose-adjusted HbA1c (IDAA1c) and C-peptide responses during the first 2 years following diagnosis of type 1 diabetes. METHODS: A secondary analysis was conducted of data collected from a randomised trial assessing the effect of intensive management initiated within 1 week of diagnosis of type 1 diabetes, in which mixed-meal tolerance tests were performed at baseline and at eight additional time points through 24 months. CGM data were collected at each visit. RESULTS: Among 67 study participants (mean age [± SD] 13.3 ± 5.7 years), HbA1c was inversely correlated with C-peptide at each time point (p < 0.001), as were changes in each measure between time points (p < 0.001). However, C-peptide at one visit did not predict the change in HbA1c at the next visit and vice versa. Higher C-peptide levels correlated with increased proportion of CGM glucose values between 3.9 and 7.8 mmol/l and lower CV (p = 0.001 and p = 0.02, respectively) but not with CGM glucose levels <3.9 mmol/l. Virtually all participants with IDAA1c < 9 retained substantial insulin secretion but when evaluated together with CGM, time in the range of 3.9-7.8 mmol/l and CV did not provide additional value in predicting C-peptide levels. CONCLUSIONS/INTERPRETATION: In the first 2 years after diagnosis of type 1 diabetes, higher C-peptide levels are associated with increased sensor glucose levels in the target range and with lower glucose variability but not hypoglycaemia. CGM metrics do not provide added value over the IDAA1c in predicting C-peptide levels

Precursors To and Pathways Through Conversion: Catalytic Experiences of Born Again Christian College Students

Born again Christians are a significant religious population in the United States, and throughout the world. The process by which a born again identity is assumed is not clearly described in the research literature. Therefore, we asked 18 born again Christian college students a series of questions designed to uncover what led to their identity of being born again. Responses fell into three overarching themes. First, participants described exposure within relationships to God’s principles. Second, participants noted the influence of introspection and reflection on their lives apart from the influence of God. Third, participants had an active response in which they reported such things as recognizing conviction by the Holy Spirit, that they decided to act on that conviction, and that they took action to follow Jesus. Findings are discussed within the framework of Cohen and Hill’s (2007) theory of religion as culture

Agrobacterium tumefaciens ExoR represses succinoglycan biosynthesis and is required for biofilm formation and motility

The ubiquitous plant pathogen Agrobacterium tumefaciens attaches efficiently to plant tissues and abiotic surfaces and can form complex biofilms. A genetic screen for mutants unable to form biofilms on PVC identified disruptions in a homologue of the exoR gene. ExoR is a predicted periplasmic protein, originally identified in Sinorhizobium meliloti, but widely conserved among alphaproteobacteria. Disruptions in the A. tumefaciens exoR gene result in severely compromised attachment to abiotic surfaces under static and flow conditions, and to plant tissues. These mutants are hypermucoid due to elevated production of the exopolysaccharide succinoglycan, via derepression of the exo genes that direct succinoglycan synthesis. In addition, exoR mutants have lost flagellar motility, do not synthesize detectable flagellin and are diminished in flagellar gene expression. The attachment deficiency is, however, complex and not solely attributable to succinoglycan overproduction or motility disruption. A. tumefaciens ExoR can function independently of the ChvG–ChvI two component system, implicated in ExoR-dependent regulation in S. meliloti. Mutations that suppress the exoR motility defect suggest a branched regulatory pathway controlling succinoglycan synthesis, motility and biofilm formation