Classification of unitary highest weight representations for non compact real forms

Using Jakobsen theorems, unitarizability in Hermitian Symmetric Spaces is discussed. The set of all missing highest weights is explicitly calculated and the construction of their corresponding highest weights vectors is studied.Comment: PDF, 35 pages (late submission

Deciphering the complexity of human non-coding promoter-proximal transcriptome.

Long non-coding RNAs (lncRNAs) have gained increasing relevance in epigenetic regulation and nuclear functional organization. High-throughput sequencing approaches have revealed frequent non-coding transcription in promoter-proximal regions. However, a comprehensive catalogue of promoter-associated RNAs (paRNAs) and an analysis of the possible interactions with neighboring genes and genomic regulatory elements are missing. Integrating data from multiple cell types and experimental platforms we identified thousands of paRNAs in the human genome. paRNAs are transcribed in both sense and antisense orientation, are mostly non-polyadenylated and retained in the cell nucleus. Transcriptional regulators, epigenetic effectors and activating chromatin marks are enriched in paRNA-positive promoters. Furthermore, paRNA-positive promoters exhibit chromatin signatures of both active promoters and enhancers. Promoters with paRNAs reside preferentially at chromatin loop boundaries, suggesting an involvement in anchor site recognition and chromatin looping. Importantly, these features are independent of the transcriptional state of neighboring genes. Thus, paRNAs may act as cis-regulatory modules with an impact on local recruitment of transcription factors, epigenetic state and chromatin loop organization. This study provides a comprehensive analysis of the promoter-proximal transcriptome and offers novel insights into the roles of paRNAs in epigenetic processes and human diseases. Genomic coordinates of predicted paRNAs are available at https://figshare.com: https://doi.org/10.6084/m9.figshare.7392791.v1 and https://doi.org/10.6084/m9.figshare.4856630.v2. Supplementary data are available at Bioinformatics online

Specific gene correction of the AGXT gene and direct cell reprogramming for the treatment of Primary Hyperoxaluria Type 1

P428 Primary Hyperoxaluria Type 1 (PH1) is an inherited rare metabolic liver disease caused by the deficiency in the alanine: glyoxylate aminotransferase enzyme (AGXT), involved in the glyoxylate metabolism. The only potentially curative treatment is organ transplantation. Thus, the development of new therapeutic approaches for the treatment of these patients appears as a priority.We propose the combination of site-specific gene correction and direct cell reprogramming for the generation of autologous phenotypically healthy induced hepatocytes (iHeps) from skin-derived fibroblast of PH1 patients. For the correction of AGXT mutations, we have designed specific gene editing tools to address gene correction by two different strategies, assisted by CRISPR/Cas9 system. Accurate specific point mutation correction (c.853T-C) has been achieved by homologydirected repair (HDR) with ssODN harbouring wild-type sequence. In the second strategy, an enhanced version ofAGXTcDNAhas been inserted near the transcription start codon of the endogenous gene, constituting an almost universal correction strategy for PH1 mutations. Direct reprogramming of fibroblasts has been conducted by overexpression of hepatic transcription factors and in vitro culture in defined media. In vitro characterization of healthy induced hepatocytes (iHeps) has demonstrated hepatic function of the reprogrammed cells. PH1 patient fibroblasts and , ,

SWI/SNF regulates a transcriptional programme that induces senescence to prevent liver cancer

Oncogene-induced senescence (OIS) is a potent tumour suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumours. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that pro-senescence therapies could be employed against SWI/SNF-mutated cancers

A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours

Enhancement of cellular senescence in tumours triggers a stable cell growth arrest and activation of an antitumour immune response that can be exploited for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers, but the majority of them are not selective and also target healthy cells. Here we developed a chemogenomic screening to identify compounds that enhance senescence in PTEN-deficient cells without affecting normal cells. By using this approach, we identified casein kinase 2 (CK2) as a pro-senescent target. Mechanistically, we show that Pten loss increases CK2 levels by activating STAT3. CK2 upregulation in Pten null tumours affects the stability of Pml, an essential regulator of senescence. However, CK2 inhibition stabilizes Pml levels enhancing senescence in Pten null tumours. Taken together, our screening strategy has identified a novel STAT3-CK2-PML network that can be targeted for pro-senescence therapy for cancer

Impact of Liver Inflammation on Bile Acid Side Chain Shortening and Amidation

Bile acid (BA) synthesis from cholesterol by hepatocytes is inhibited by inflammatory cytokines. Whether liver inflammation also affects BA side chain shortening and conjugation was investigated. In human liver cell lines (IHH, HepG2, and HepaRG), agonists of nuclear receptors including the farnesoid X receptor (FXR), liver X receptor (LXR), and peroxisome proliferator-activated receptors (PPARs) did not affect the expression of BA-related peroxisomal enzymes. In contrast, hepatocyte nuclear factor 4? (HNF4?) inhibition down-regulated acyl-CoA oxidase 2 (ACOX2). ACOX2 was repressed by fibroblast growth factor 19 (FGF19), which was prevented by extracellular signal-regulated kinase (ERK) pathway inhibition. These changes were paralleled by altered BA synthesis (HPLC-MS/MS). Cytokines able to down-regulate cholesterol-7?-hydroxylase (CYP7A1) had little effect on peroxisomal enzymes involved in BA synthesis except for ACOX2 and bile acid-CoA:amino acid N-acyltransferase (BAAT), which were down-regulated, mainly by oncostatin M (OSM). This effect was prevented by Janus kinase (JAK) inhibition, which restored BA side chain shortening and conjugation. The binding of OSM to the extracellular matrix accounted for a persistent effect after culture medium replacement. In silico analysis of four databases (n = 201) and a validation cohort (n = 90) revealed an inverse relationship between liver inflammation and ACOX2/BAAT expression which was associated with changes in HNF4? levels. In conclusion, BA side chain shortening and conjugation are inhibited by inflammatory effectors. However, other mechanisms involved in BA homeostasis counterbalance any significant impact on the serum BA profile

A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers.

Long noncoding RNAs are emerging players in the epigenetic machinery with key roles in development and diseases. Here we uncover a complex network comprising a promoter-associated noncoding RNA (paRNA), microRNA and epigenetic regulators that controls transcription of the tumour suppressor E-cadherin in epithelial cancers. E-cadherin silencing relies on the formation of a complex between the paRNA and microRNA-guided Argonaute 1 that, together, recruit SUV39H1 and induce repressive chromatin modifications in the gene promoter. A single nucleotide polymorphism (rs16260) linked to increased cancer risk alters the secondary structure of the paRNA, with the risk allele facilitating the assembly of the microRNA-guided Argonaute 1 complex and gene silencing. Collectively, these data demonstrate the role of a paRNA in E-cadherin regulation and the impact of a noncoding genetic variant on its function. Deregulation of paRNA-based epigenetic networks may contribute to cancer and other diseases making them promising targets for drug discovery

Análisis arqueosismológico del conjunto arqueológico romano de Mulva- Munigua (Sevilla, España). Resultados preliminares

El conjunto arqueológico romano de Mulva-Munigua (Sevilla, España) presenta daños en las edificaciones que pueden ser interpretadas como resultado de la ocurrencia de un evento sísmico (Efectos Arqueológicos de los Terremotos: EAEs) a finales del siglo III A.D., fecha coincidente con el inicio del periodo de declive económico de este asentamiento romano. Para intentar establecer el posible origen sísmico de las deformaciones, se ha procedido al inventario y análisis de las estructuras deformadas presentes en el yacimiento. No obstante, algunas de estas deformaciones también se pueden interpretar como resultado de procesos gravitaciones asociados a la ladera Este de la colina sobre la que se sitúa parte del yacimiento. Las direcciones de máxima deformación (ey) obtenidas del análisis de EAEs indica dos direcciones preferentes de la deformación (o movimiento preferente del terreno): NNO-SSE y ENEOSO. Aunque los datos presentan una dispersión importante, se puede establecer que la orientación principal NNO-SSE es compatible con un evento sísmico situado en el borde norte del Valle del Guadalquivir. La orientación ENE-OSO podría relacionarse con un evento posterior, o más seguramente con procesos de ladera de carácter cosísmico o no.The Roman archaeological site of Mulva-Munigua (Sevilla, Spain) displays building damage features suggesting a seismic origin (Earthquake Archaeological Effects: EAEs). The proposed seismic event could be tentatively dated in the late 3rd century AD, coinciding with the beginning of the economic fall of the Roman Empire at Iberia. However, some of the recorded EAEs can be also interpreted as a result of intervening slope movements in the eastern hillslope of this roman site. The inventory and analysis of the proposed EAEs make possible to discern between seismic oriented damage and other causes. In spite of the data show a significant dispersion, their analysis result in two different orientations of maximum deformation (ey) or preferential ground movement: NNW-SSE and ENE-WSW. The main ey orientation (NNW-SSE) can be tentatively related to a seismic event occurred in the environs of the northern border of the Guadalquivir Depression. The secondary orientation (ENE-WSW) can be interpreted as a consequence of latter slope movements triggered (or not) by other ancient earthquakes

An alien ectosymbiotic branchiobdellidan (Annelida: Clitellata) adopting exotic crayfish: a biological co-invasion with unpredictable consequences

Invasive alien species present a global threat to biodiversity, particularly where pathogens and symbionts are involved. Branchiobdellidans are clitellate annelids with an obligate ectosymbiotic association primarily on astacoidean crayfish. There are several examples of branchiobdellidan species adopting a geographically exotic host where endemic and exotic crayfishes cohabit the same water body. The first records of a western North American branchiobdellidan, Xironogiton victoriensis, adopting the eastern North American crayfish, Procambarus clarkii, in 2 river basins in Spain provide further evidence of the ectosymbionts’ tolerance to adopt an exotic host. Given worldwide translocations of these and other commercial crayfish species, limnologists and agency managers need to be alert for further introductions of X. victoriensis and other branchiobdellidans. Impacts of these exotic ectosymbionts on habitat and biota at a new location are unknown, as are their consequences on native biodiversit

Sterile neutrino portal to Dark Matter I: the U(1) B−L case

In this paper we explore the possibility that the sterile neutrino and Dark Matter sectors in the Universe have a common origin. We study the consequences of this assumption in the simple case of coupling the dark sector to the Standard Model via a global U(1)B−L, broken down spontaneously by a dark scalar. This dark scalar provides masses to the dark fermions and communicates with the Higgs via a Higgs portal coupling. We find an interesting interplay between Dark Matter annihilation to dark scalars — the CP-even that mixes with the Higgs and the CP-odd which becomes a Goldstone boson, the Majoron — and heavy neutrinos, as well as collider probes via the coupling to the Higgs. Moreover, Dark Matter annihilation into sterile neutrinos and its subsequent decay to gauge bosons and quarks, charged leptons or neutrinos lead to indirect detection signatures which are close to current bounds on the gamma ray flux from the galactic center and dwarf galaxies