Regulation of NF-κB activity through lysine monomethylation of p65

NF-κB is a key activator of inflammatory and immune responses with important pathological roles in cancer, heart disease, and autoimmune diseases. Transcriptional activity of NF-κB is regulated by different posttranslational modifications. Here, we report a novel mechanism of NF-κB regulation through lysine monomethylation by SET9 methyltransferase. Set9 specifically methylates p65 at lysine 37. Both TNFα and IL-1β treatments induced methylation of p65. Methylated p65 is restricted to the nucleus and this modification regulates the promoter binding of p65. Moreover, Set9 mediated methylation of p65 is required for the expression of a subset of NF-κB target genes in response to TNFα stimulation

Building the Brazilian Academic Genealogy Tree

Along the history, many researchers provided remarkable contributions to science, not only advancing knowledge but also in terms of mentoring new scientists. Currently, identifying and studying the formation of researchers over the years is a challenging task as current repositories of theses and dissertations are cataloged in a decentralized way through many local digital libraries. Following our previous work in which we created and analyzed a large collection of genealogy trees extracted from NDLTD, in this paper we focus our attention on building such trees for the Brazilian research community. For this, we use data from the Lattes Platform, an internationally renowned initiative from CNPq, the Brazilian National Council for Scientific and Technological Development, for managing information about individual researchers and research groups in Brazil

EHMT1 Protein Binds to Nuclear Factor-κB p50 and Represses Gene Expression

Transcriptional homeostasis relies on the balance between positive and negative regulation of gene transcription. Methylation of histone H3 lysine 9 (H3K9) is commonly correlated with gene repression. Here, we report that a euchromatic H3K9 methyltransferase, EHMT1, functions as a negative regulator in both the NF-κB- and type I interferon-mediated gene induction pathways. EHMT1 catalyzes H3K9 methylation at promoters of NF-κB target genes. Moreover, EHMT1 interacts with p50, and, surprisingly, p50 appears to repress the expression of type I interferon genes and genes activated by type I interferons by recruiting EHMT1 to catalyze H3K9 methylation at their promoter regions. Silencing the expression of EHMT1 by RNA interference enhances expression of a subset NF-κB-regulated genes, augments interferon production, and augments antiviral immunity

Parameterized Model-Checking for Timed-Systems with Conjunctive Guards (Extended Version)

In this work we extend the Emerson and Kahlon's cutoff theorems for process skeletons with conjunctive guards to Parameterized Networks of Timed Automata, i.e. systems obtained by an \emph{apriori} unknown number of Timed Automata instantiated from a finite set $U_1, \dots, U_n$ of Timed Automata templates. In this way we aim at giving a tool to universally verify software systems where an unknown number of software components (i.e. processes) interact with continuous time temporal constraints. It is often the case, indeed, that distributed algorithms show an heterogeneous nature, combining dynamic aspects with real-time aspects. In the paper we will also show how to model check a protocol that uses special variables storing identifiers of the participating processes (i.e. PIDs) in Timed Automata with conjunctive guards. This is non-trivial, since solutions to the parameterized verification problem often relies on the processes to be symmetric, i.e. indistinguishable. On the other side, many popular distributed algorithms make use of PIDs and thus cannot directly apply those solutions

Pseudomonas aeruginosa Enhances Production of a Non-Alginate Exopolysaccharide during Long-Term Colonization of the Cystic Fibrosis Lung

The gram-negative opportunistic pathogen Pseudomonas aeruginosa is the primary cause of chronic respiratory infections in individuals with the heritable disease cystic fibrosis (CF). These infections can last for decades, during which time P. aeruginosa has been proposed to acquire beneficial traits via adaptive evolution. Because CF lacks an animal model that can acquire chronic P. aeruginosa infections, identifying genes important for long-term in vivo fitness remains difficult. However, since clonal, chronological samples can be obtained from chronically infected individuals, traits undergoing adaptive evolution can be identified. Recently we identified 24 P. aeruginosa gene expression traits undergoing parallel evolution in vivo in multiple individuals, suggesting they are beneficial to the bacterium. The goal of this study was to determine if these genes impact P. aeruginosa phenotypes important for survival in the CF lung. By using a gain-of-function genetic screen, we found that 4 genes and 2 operons undergoing parallel evolution in vivo promote P. aeruginosa biofilm formation. These genes/operons promote biofilm formation by increasing levels of the non-alginate exopolysaccharide Psl. One of these genes, phaF, enhances Psl production via a post-transcriptional mechanism, while the other 5 genes/operons do not act on either psl transcription or translation. Together, these data demonstrate that P. aeruginosa has evolved at least two pathways to over-produce a non-alginate exopolysaccharide during long-term colonization of the CF lung. More broadly, this approach allowed us to attribute a biological significance to genes with unknown function, demonstrating the power of using evolution as a guide for targeted genetic studies.open6

Effect of COVID-19 vaccination on transmission of Alpha and Delta variants

BACKGROUND: Before the emergence of the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccination reduced transmission of SARS-CoV-2 from vaccinated persons who became infected, potentially by reducing viral loads. Although vaccination still lowers the risk of infection, similar viral loads in vaccinated and unvaccinated persons who are infected with the delta variant call into question the degree to which vaccination prevents transmission. METHODS: We used contact-testing data from England to perform a retrospective observational cohort study involving adult contacts of SARS-CoV-2–infected adult index patients. We used multivariable Poisson regression to investigate associations between transmission and the vaccination status of index patients and contacts and to determine how these associations varied with the B.1.1.7 (alpha) and delta variants and time since the second vaccination. RESULTS: Among 146,243 tested contacts of 108,498 index patients, 54,667 (37%) had positive SARS-CoV-2 polymerase-chain-reaction (PCR) tests. In index patients who became infected with the alpha variant, two vaccinations with either BNT162b2 or ChAdOx1 nCoV-19 (also known as AZD1222), as compared with no vaccination, were independently associated with reduced PCR positivity in contacts (adjusted rate ratio with BNT162b2, 0.32; 95% confidence interval [CI], 0.21 to 0.48; and with ChAdOx1 nCoV-19, 0.48; 95% CI, 0.30 to 0.78). Vaccine-associated reductions in transmission of the delta variant were smaller than those with the alpha variant, and reductions in transmission of the delta variant after two BNT162b2 vaccinations were greater (adjusted rate ratio for the comparison with no vaccination, 0.50; 95% CI, 0.39 to 0.65) than after two ChAdOx1 nCoV-19 vaccinations (adjusted rate ratio, 0.76; 95% CI, 0.70 to 0.82). Variation in cycle-threshold (Ct) values (indicative of viral load) in index patients explained 7 to 23% of vaccine-associated reductions in transmission of the two variants. The reductions in transmission of the delta variant declined over time after the second vaccination, reaching levels that were similar to those in unvaccinated persons by 12 weeks in index patients who had received ChAdOx1 nCoV-19 and attenuating substantially in those who had received BNT162b2. Protection in contacts also declined in the 3-month period after the second vaccination. CONCLUSIONS: Vaccination was associated with a smaller reduction in transmission of the delta variant than of the alpha variant, and the effects of vaccination decreased over time. PCR Ct values at diagnosis of the index patient only partially explained decreased transmission. (Funded by the U.K. Government Department of Health and Social Care and others.

Complexity and Expressivity of Branching- and Alternating-Time Temporal Logics with Finitely Many Variables

We show that Branching-time temporal logics CTL and CTL*, as well as Alternating-time temporal logics ATL and ATL*, are as semantically expressive in the language with a single propositional variable as they are in the full language, i.e., with an unlimited supply of propositional variables. It follows that satisfiability for CTL, as well as for ATL, with a single variable is EXPTIME-complete, while satisfiability for CTL*, as well as for ATL*, with a single variable is 2EXPTIME-complete,--i.e., for these logics, the satisfiability for formulas with only one variable is as hard as satisfiability for arbitrary formulas.Comment: Prefinal version of the published pape

Genetic variation associated with hypersensitivity to mercury

OBJECTIVES: Very little is known about mechanisms of idiosyncratic sensitivity to the damaging effects of mercury (Hg); however, there is likely a genetic component. The aim of the present study was to search for genetic variation in genes thought to be involved in Hg metabolism and transport in a group of individuals identified as having elevated Hg sensitivity compared to a normal control group. MATERIALS AND METHODS: Survivors of pink disease (PD; infantile acrodynia) are a population of clinically identifiable individuals who are Hg sensitive. In the present study, single nucleotide polymorphisms in genes thought to be involved in Hg transport and metabolism were compared across two groups: (i) PD survivors (n = 25); and (ii) age- and sex-matched healthy controls (n = 25). RESULTS: Analyses revealed significant differences between groups in genotype frequencies for rs662 in the gene encoding paraoxanase 1 (PON1) and rs1801131 in the gene encoding methylenetetrahydrofolate reductase (MTHFR). CONCLUSIONS: We have identified two genetic polymorphisms associated with increased sensitivity to Hg. Genetic variation in MTHFR and PON1 significantly differentiated a group formerly diagnosed with PD (a condition of Hg hypersensitivity) with age- and gender-matched healthy controls

Conservation laws and tachyon potentials in the sliver frame

Conservation laws have provided an elegant and efficient tool to evaluate the open string field theory interaction vertex, they have been originally implemented in the case where the string field is expanded in the Virasoro basis. In this work we derive conservation laws in the case where the string field is expanded in the so-called sliver $\mathcal{L}_0$-basis. As an application of these conservation laws derived in the sliver frame, we compute the open string field action relevant to the tachyon condensation and in order to present not only an illustration but also an additional information, we evaluate the action without imposing a gauge choice.Comment: 26 pages, some typos fixed, comments added, references adde

Graviton 1-loop partition function for 3-dimensional massive gravity

The graviton 1-loop partition function in Euclidean topologically massive gravity (TMG) is calculated using heat kernel techniques. The partition function does not factorize holomorphically, and at the chiral point it has the structure expected from a logarithmic conformal field theory. This gives strong evidence for the proposal that the dual conformal field theory to TMG at the chiral point is indeed logarithmic. We also generalize our results to new massive gravity.Comment: 19 pages, v2: major revision, considerably stronger conclusions, added comparison with LCFT partition function, confirmation of LCFT conjecture, added autho