Loss of Endometrial Plasticity in Recurrent Pregnancy Loss

© 2015 AlphaMed Press.Menstruation drives cyclic activation of endometrial progenitor cells, tissue regeneration, and maturation of stromal cells, which differentiate into specialized decidual cells prior to and during pregnancy. Aberrant responsiveness of human endometrial stromal cells (HESCs) to deciduogenic cues is strongly associated with recurrent pregnancy loss (RPL), suggesting a defect in cellular maturation. MeDIP-seq analysis of HESCs did not reveal gross perturbations in CpG methylation in RPL cultures, although quantitative differences were observed in or near genes that are frequently deregulated in vivo. However, RPL was associated with a marked reduction in methylation of defined CA-rich motifs located throughout the genome but enriched near telomeres. Non-CpG methylation is a hallmark of cellular multipotency. Congruently, we demonstrate that RPL is associated with a deficiency in endometrial clonogenic cell populations. Loss of epigenetic stemness features also correlated with intragenic CpG hypomethylation and reduced expression of HMGB2, coding high mobility group protein 2. We show that knockdown of this sequence-independent chromatin protein in HESCs promotes senescence and impairs decidualization, exemplified by blunted time-dependent secretome changes. Our findings indicate that stem cell deficiency and accelerated stromal senescence limit the differentiation capacity of the endometrium and predispose for pregnancy failure. Stem Cells 2016;34:346-356 Recurrent pregnancy loss is caused by endometrial stem cell deficiency, triggering heightened tissue senescence and impaired decidualization

Gene Expression Profiling Identified High-mobility Group AT-hook (HMGA2) as Being Frequently Upregulated in Esophageal Squamous Cell Carcinoma

Background: Esophageal cancer is one of the most deadly malignancies worldwide and esophageal squamous cell carcinoma (ESCC) is the most frequent type. Methods: We identified up-regulated genes from gene expression profiles of HKESC-4 cell line, its parental tumor tissues, non-tumoral esophageal epithelia and lymph nodes with metastatic carcinoma using Human Genome U133 Plus 2.0 microarray. Results: Four genes [High-mobility group AT-hook 2 (HMGA2), paternally expressed 10 (PEG10), SH3 and multiple ankyrin repeat domains 2 (SHANK2) and WNT1 inducible signaling pathway protein 3 (WISP3)] were selected for further validation with real-time quantitative polymerase chain reaction (qPCR) in a panel of ESCC cell lines and clinical specimens. HMGA2 was found to be overexpressed in the panel of ESCC cell lines tested. By using immunohistochemistry, HMGA2 was found to be up-regulated in 70% of ESCC tissues (21 out of 30 cases). Conclusion: This study demonstrates successful use of gene microarray to identify and reveal HMGA2 as a novel and consistently overexpressed gene in ESCC cell lines and clinical samples.published_or_final_versio

The VIMOS Ultra-Deep Survey: A major merger origin for the high fraction of galaxies at 2 < z < 6 with two bright clumps

(Abridged) The properties of stellar clumps in star forming galaxies and their evolution over the redshift range $2\lesssim z \lesssim 6$ are presented and discussed in the context of the build-up of massive galaxies at early cosmic times. We use HST/ACS images of galaxies with spectroscopic redshifts from the VIMOS Ultra Deep Survey (VUDS) to identify clumps within a 20 kpc radius. We find that the population of galaxies with more than one clump is dominated by galaxies with two clumps, representing $\sim21-25$\% of the population, while the fraction of galaxies with 3, or 4 and more, clumps is 8-11 and 7-9\%, respectively. The fraction of clumpy galaxies is in the range $\sim35-55\%$ over $2<z<6$, increasing at higher redshifts, indicating that the fraction of irregular galaxies remains high up to the highest redshifts. The large and bright clumps (M$_{\star}\sim10^9$ up to $\sim10^{10}$M$_\odot$) are found to reside predominantly in galaxies with two clumps. Smaller and lower luminosity clumps ($\log_{10}\left(M_{\star}/\mathrm{M_\odot}\right)<9$) are found in galaxies with three clumps or more. We interpret these results as evidence for two different modes of clump formation working in parallel. The small low luminosity clumps are likely the result of disc fragmentation, with violent disc instabilities (VDI) forming several long-lived clumps in-situ, as suggested from simulations. A fraction of these clumps is also likely coming from minor mergers. The clumps in the dominating population of galaxies with two clumps are significantly more massive and have properties akin to those in merging pairs observed at similar redshifts; they appear as more massive than the most massive clumps observed in VDI numerical simulations

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a.

p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate

Characterization of star-forming dwarf galaxies at 0.1 ≲ z ≲ 0.9 in VUDS: Probing the low-mass end of the mass-metallicity relation

We present the discovery and spectrophotometric characterization of a large sample of 164 faint ($i_{AB}$ $\sim$ $23$-$25$ mag) star-forming dwarf galaxies (SFDGs) at redshift $0.13$ $\leq z \leq$ $0.88$ selected by the presence of bright optical emission lines in the VIMOS Ultra Deep Survey (VUDS). We investigate their integrated physical properties and ionization conditions, which are used to discuss the low-mass end of the mass-metallicity relation (MZR) and other key scaling relations. We use optical VUDS spectra in the COSMOS, VVDS-02h, and ECDF-S fields, as well as deep multiwavelength photometry, to derive stellar masses, star formation rates (SFR) and gas-phase metallicities. The VUDS SFDGs are compact (median $r_{e}$ $\sim$ $1.2$ kpc), low-mass ($M_{*}$ $\sim$ $10^7-10^9$ $M_{\odot}$) galaxies with a wide range of star formation rates (SFR($H\alpha$) $\sim 10^{-3}-10^{1}$ $M_{\odot}/yr$) and morphologies. Overall, they show a broad range of subsolar metallicities (12+log(O/H)=$7.26$-$8.7$; $0.04$ $\lesssim Z/Z_{\odot} \lesssim$ $1$). The MZR of SFDGs shows a flatter slope compared to previous studies of galaxies in the same mass range and redshift. We find the scatter of the MZR partly explained in the low mass range by varying specific SFRs and gas fractions amongst the galaxies in our sample. Compared with simple chemical evolution models we find that most SFDGs do not follow the predictions of a "closed-box" model, but those from a gas regulating model in which gas flows are considered. While strong stellar feedback may produce large-scale outflows favoring the cessation of vigorous star formation and promoting the removal of metals, younger and more metal-poor dwarfs may have recently accreted large amounts of fresh, very metal-poor gas, that is used to fuel current star formation

Changes in anti-viral effectiveness of interferon after dose reduction in chronic hepatitis c patients: a case control study

BACKGROUND: High dose interferon induction treatment of hepatitis C viral infection blocks viral production over 95%. Since dose reduction is often performed due to clinical considerations, the effect of dose reduction on hepatitis C virus kinetics was studied. METHODS: A new model that allowed longitudinal changes in the parameters of viral dynamics was used in a group of genotype-1 patients (N = 15) with dose reduction from 10 to 3 million units of interferon daily in combination with ribavirin, in comparison to a control group (N = 9) with no dose reduction. RESULTS: Dose reduction gave rise to a complex viral kinetic pattern, which could be only explained by a decrease in interferon effectiveness in blocking virion production. The benefit of the rapid initial viral decline following the high induction dose is lost after dose reduction. In addition, in some patients also the second phase viral decline slope, which is highly predictive of success of treatment, was impaired by the dose reduction resulting in smaller percentage of viral clearance in the dose reduction group. CONCLUSIONS: These findings, while explaining the failure of many induction schedules, suggest that for genotype-1 patients induction therapy should be continued till HCVRNA negativity in serum in order to increase the sustained response rate for chronic hepatitis C

The VIMOS Ultra Deep Survey: The role of HI kinematics and HI column density on the escape of Lyα photons in star-forming galaxies at 2 < z < 4

© 2017 ESO. Aims. We wish to assess the role of kinematics and neutral hydrogen column density in the escape and distribution of Lya photons. Methods. We selected a sample of 76 Lya emitting galaxies from the VIMOS Ultra Deep Survey (VUDS) at 2 = z = 4. We estimated the velocity of the neutral gas flowing out of the interstellar medium as the velocity offset, δv, between the systemic redshift (zsys) and the center of low-ionization absorption line systems (LIS). To increase the S/N of VUDS spectra, we stacked subsamples defined based on median values of their photometric and spectroscopic properties. We measured the systemic redshift from the rest-frame UV spectroscopic data using the CIII]1908 nebular emission line, and we considered SiII1526 as the highest signal-to-noise LIS line. We calculated the Lya peak shift with respect to the zsys, the EW(Lya), and the Lya spatial extension, Ext(Lya-C), from the in the 2D stacked spectra. Results. The galaxies that are faint in the rest-frame UV continuum, strong in Lya and CIII] , with compact UV morphology, and localized in an underdense environment are characterized by outflow velocities of the order of a few hundreds of km s -1 . The subsamples with smaller δv are characterized by larger Lya peak shifts, larger Ext(Lya-C), and smaller EW(Lya). In general we find that EW(Lya) anti-correlates with Ext(Lya-C) and Lya peak shift. Conclusions. We interpret these trends using a radiative-transfer shell model. The model predicts that an HI gas with a column density larger than 1020 cm -2 is able to produce Lya peak shifts larger than > 300 km s -1 . An ISM with this value of NHI would favour a large amount of scattering events, especially when the medium is static, so it can explain large values of Ext(Lya-C) and small EW(Lya). On the contrary, an ISM with a lower NHI, but large velocity outflows would lead to a Lya spatial profile peaked at the galaxy center (i.e. low values of Ext(Lya-C)) and to a large EW(Lya), as we see in our data. Our results and their interpretation via radiative-transfer models tell us that it is possible to use Lya to study the properties of the HI gas. Also, the fact that Lya emitters are characterized by large δv could give hints about their stage of evolution in the sense that they could be experiencing short bursts of star formation that push strong outflows.This work is supported by funding from the European Research Council Advanced Grant ERC–2010–AdG–268107–EARLY and by INAF Grants PRIN 2010, PRIN 2012, and PICS 2013. This work is based on data products made available at the CESAM data center, Laboratoire d’Astrophysique de Marseille, France. R.A. acknowledges support from the ERC Advanced Grant 695671 “QUENCH” and I.O. from the Czech Science Foundation grant 17-06217Y

A direct physical interaction between Nanog and Sox2 regulates embryonic stem cell self-renewal

Embryonic stem (ES) cell self-renewal efficiency is determined by the Nanog protein level. However, the protein partners of Nanog that function to direct self-renewal are unclear. Here, we identify a Nanog interactome of over 130 proteins including transcription factors, chromatin modifying complexes, phosphorylation and ubiquitination enzymes, basal transcriptional machinery members, and RNA processing factors. Sox2 was identified as a robust interacting partner of Nanog. The purified Nanog–Sox2 complex identified a DNA recognition sequence present in multiple overlapping Nanog/Sox2 ChIP-Seq data sets. The Nanog tryptophan repeat region is necessary and sufficient for interaction with Sox2, with tryptophan residues required. In Sox2, tyrosine to alanine mutations within a triple-repeat motif (S X T/S Y) abrogates the Nanog–Sox2 interaction, alters expression of genes associated with the Nanog-Sox2 cognate sequence, and reduces the ability of Sox2 to rescue ES cell differentiation induced by endogenous Sox2 deletion. Substitution of the tyrosines with phenylalanine rescues both the Sox2–Nanog interaction and efficient self-renewal. These results suggest that aromatic stacking of Nanog tryptophans and Sox2 tyrosines mediates an interaction central to ES cell self-renewal

The effect of tightly-bound water molecules on scaffold diversity in computer-aided de novo ligand design of CDK2 inhibitors

We have determined the effects that tightly bound water molecules have on the de novo design of cyclin-dependent kinase-2 (CDK2) ligands. In particular, we have analyzed the impact of a specific structural water molecule on the chemical diversity and binding mode of ligands generated through a de novo structure-based ligand generation method in the binding site of CDK2. The tightly bound water molecule modifies the size and shape of the binding site and we have found that it also imposed constraints on the observed binding modes of the generated ligands. This in turn had the indirect effect of reducing the chemical diversity of the underlying molecular scaffolds that were able to bind to the enzyme satisfactorily

Extended Interferon-Alpha Therapy Accelerates Telomere Length Loss in Human Peripheral Blood T Lymphocytes

BACKGROUND: Type I interferons have pleiotropic effects on host cells, including inhibiting telomerase in lymphocytes and antiviral activity. We tested the hypothesis that long-term interferon treatment would result in significant reduction in average telomere length in peripheral blood T lymphocytes. METHODS/PRINCIPAL FINDINGS: Using a flow cytometry-based telomere length assay on peripheral blood mononuclear cell samples from the Hepatitis-C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study, we measured T cell telomere lengths at screening and at months 21 and 45 in 29 Hepatitis-C virus infected subjects. These subjects had failed to achieve a sustained virologic response following 24 weeks of pegylated-interferon-alpha plus ribavirin treatment and were subsequently randomized to either a no additional therapy group or a maintenance dose pegylated-IFNalpha group for an additional 3.5 years. Significant telomere loss in naive T cells occurred in the first 21 months in the interferon-alpha group. Telomere losses were similar in both groups during the final two years. Expansion of CD8(+)CD45RA(+)CD57(+) memory T cells and an inverse correlation of alanine aminotransferase levels with naive CD8(+) T cell telomere loss were observed in the control group but not in the interferon-alpha group. Telomere length at screening inversely correlated with Hepatitis-C viral load and body mass index. CONCLUSIONS/SIGNIFICANCE: Sustained interferon-alpha treatment increased telomere loss in naive T cells, and inhibited the accumulation of T cell memory expansions. The durability of this effect and consequences for immune senescence need to be defined