Monotonic Distributive Semilattices

In the study of algebras related to non-classical logics, (distributive) semilattices are always present in the background. For example, the algebraic semantic of the {→, ∧, ⊤}-fragment of intuitionistic logic is the variety of implicative meet-semilattices (Chellas 1980; Hansen 2003). In this paper we introduce and study the class of distributive meet-semilattices endowed with a monotonic modal operator m. We study the representation theory of these algebras using the theory of canonical extensions and we give a topological duality for them. Also, we show how our new duality extends to some particular subclasses.Fil: Celani, Sergio Arturo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Exactas. Departamento de Matemática; ArgentinaFil: Menchón, María Paula. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Exactas. Departamento de Matemática; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Primary skin fibroblasts as a model of Parkinson's disease

Parkinson's disease is the second most frequent neurodegenerative disorder. While most cases occur sporadic mutations in a growing number of genes including Parkin (PARK2) and PINK1 (PARK6) have been associated with the disease. Different animal models and cell models like patient skin fibroblasts and recombinant cell lines can be used as model systems for Parkinson's disease. Skin fibroblasts present a system with defined mutations and the cumulative cellular damage of the patients. PINK1 and Parkin genes show relevant expression levels in human fibroblasts and since both genes participate in stress response pathways, we believe fibroblasts advantageous in order to assess, e.g. the effect of stressors. Furthermore, since a bioenergetic deficit underlies early stage Parkinson's disease, while atrophy underlies later stages, the use of primary cells seems preferable over the use of tumor cell lines. The new option to use fibroblast-derived induced pluripotent stem cells redifferentiated into dopaminergic neurons is an additional benefit. However, the use of fibroblast has also some drawbacks. We have investigated PARK6 fibroblasts and they mirror closely the respiratory alterations, the expression profiles, the mitochondrial dynamics pathology and the vulnerability to proteasomal stress that has been documented in other model systems. Fibroblasts from patients with PARK2, PARK6, idiopathic Parkinson's disease, Alzheimer's disease, and spinocerebellar ataxia type 2 demonstrated a distinct and unique mRNA expression pattern of key genes in neurodegeneration. Thus, primary skin fibroblasts are a useful Parkinson's disease model, able to serve as a complement to animal mutants, transformed cell lines and patient tissues

Regional variation in hospitalization for stroke among Asians/Pacific Islanders in the United States: a nationwide retrospective cohort study

BACKGROUND: In Asia, stroke incidence varies dramatically from country to country. Little is known about stroke incidence in Asians/Pacific Islanders in the US, where regional heterogeneity in Asian/Pacific Islander sub-populations is great. We sought to characterize both the national and regional incidences of first and recurrent hospitalized acute ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage in Asians/Pacific Islanders compared to non-Hispanic whites. METHODS: We used the National Inpatient Sample of the 1997 Healthcare Cost and Utilization Project. It is a 20% stratified sample of hospitalizations to nonfederal hospitals in the US. National and regional projections were made using sampling weights specific for patients and hospitals. We identified stroke subtypes using previously validated ICD-9 codes. Age-adjusted incidence rates were calculated using the direct method with the US population in 2000 as the standard. RESULTS: There were 169,386 stroke hospitalizations in the database. Nationally, compared to whites, Asians/Pacific Islanders were more likely to have subarachnoid hemorrhage (incidence rate ratio {RR} female: 1.53, 95% CI 1.41–1.65; male RR: 1.13, 95% CI 1.00–1.27) and intracerebral hemorrhage (female RR 1.29, 95% CI 1.22–1.36; male RR: 1.58, 95% CI 1.50–1.67). However, when examined by geographic regions, Asians/Pacific Islanders had higher incidence rates of subarachnoid hemorrhage and intracerebral hemorrhage predominantly in the West, and lower rates of stroke elsewhere. CONCLUSION: Stroke incidence varies 3-fold among Asians/Pacific Islanders residing in different US regions. Geographic variation is less dramatic in whites. Whether genetic or cultural differences are responsible for dramatic heterogeneity among Asian/Pacific Islander populations is unclear and deserves further study

The Role of p300 Histone Acetyltransferase in UV-Induced Histone Modifications and MMP-1 Gene Transcription

Matrix metalloproteinase (MMP)-1 promotes ultraviolet (UV)-triggered long-term detrimental effects such as cancer formation and premature skin aging. Although histone modifications may play a crucial role in the transcriptional regulation of MMP-1, the relationship between UV-induced histone modification and MMP-1 expression is not completely understood. Here, we identify regulators of histone acetylation that may link UV-mediated DNA damage and MMP-1 induction by UV in cultured human dermal fibroblasts (HDFs) in vitro. UV irradiation of HDFs induced MMP-1 expression and increased the level of phosphorylation of H2AX (γ-H2AX), p53 and the acetylation of histone H3 (acetyl-H3). Total histone deacetylase (HDAC) enzymatic activity was decreased by UV irradiation, while histone acetyltransferase (HAT) activity was increased. Suppression of p300 histone acetyltransferase (p300HAT) activity by the p300HAT inhibitor anacardic acid (AA) or by down-regulation of p300 by siRNA prevented UV-induced MMP-1 expression and inhibited UV-enhanced γ-H2AX, p53 level, and acetyl-H3. Using chromatin immunoprecipitation assays, we observed that γ-H2AX, p53, acetyl-H3, p300 and c-Jun were consistently recruited by UV to a distinct region (−2067/−1768) adjacent to the p300 binding site (−1858/−1845) in the MMP-1 promoter. In addition, these recruitments of γ-H2AX, p53, acetyl-H3, p300 and c-Jun to the p300-2 site were significantly abrogated by post-treatment with AA. Furthermore, overexpression of p300 increased the basal and UV-induced MMP-1 promoter activity. Our results suggest that p300HAT plays a critical role in the transcriptional regulation of MMP-1 by UV

Loss of NOTCH2 Positively Predicts Survival in Subgroups of Human Glial Brain Tumors

The structural complexity of chromosome 1p centromeric region has been an obstacle for fine mapping of tumor suppressor genes in this area. Loss of heterozygosity (LOH) on chromosome 1p is associated with the longer survival of oligodendroglioma (OD) patients. To test the clinical relevance of 1p loss in glioblastomas (GBM) patients and identifiy the underlying tumor suppressor locus, we constructed a somatic deletion map on chromosome 1p in 26 OG and 118 GBM. Deletion hotspots at 4 microsatellite markers located at 1p36.3, 1p36.1, 1p22 and 1p11 defined 10 distinct haplotypes that were related to patient survival. We found that loss of 1p centromeric marker D1S2696 within NOTCH2 intron 12 was associated with favorable prognosis in OD (P = 0.0007) as well as in GBM (P = 0.0175), while 19q loss, concomitant with 1p LOH in OD, had no influence on GBM survival (P = 0.918). Assessment of the intra-chromosomal ratio between NOTCH2 and its 1q21 pericentric duplication N2N (N2/N2N-test) allowed delineation of a consistent centromeric breakpoint in OD that also contained a minimally lost area in GBM. OD and GBM showed distinct deletion patterns that converged to the NOTCH2 gene in both glioma subtypes. Moreover, the N2/N2N-test disclosed homozygous deletions of NOTCH2 in primary OD. The N2/N2N test distinguished OD from GBM with a specificity of 100% and a sensitivity of 97%. Combined assessment of NOTCH2 genetic markers D1S2696 and N2/N2N predicted 24-month survival with an accuracy (0.925) that is equivalent to histological classification combined with the D1S2696 status (0.954) and higher than current genetic evaluation by 1p/19q LOH (0.762). Our data propose NOTCH2 as a powerful new molecular test to detect prognostically favorable gliomas

BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-κB pathway

By diversifying antibody biological effector functions, class switch DNA recombination has a central role in the maturation of the antibody response. Here we show that BCR-signalling synergizes with Toll-like receptor (TLR) signalling to induce class switch DNA recombination. BCR-signalling activates the non-canonical NF-κB pathway and enhances the TLR-dependent canonical NF-κB pathway, thereby inducing activation-induced cytidine deaminase (AID), which is critical for class switch DNA recombination. Escherichia coli lipopolysaccharide (LPS) triggers dual TLR4/BCR-signalling and induces hallmarks of BCR-signalling, including CD79a phosphorylation and Ca2+ mobilization, and activates both the NF-κB pathways to induce AID and class switch DNA recombination in a PI(3)K p85α-dependent fashion. CD40-signalling activates the two NF-κB pathways to induce AID and class switch DNA recombination independent of BCR-signalling. Finally, dual BCR/TLR-engaging NP–lipopolysaccharide effectively elicits class-switched NP-specific IgG3 and IgG2b in mice. Thus, by integrating signals of the non-canonical and canonical NF-κB pathways, BCR and TLRs synergize to induce AID and T-cell-independent class switch DNA recombination

Cdc48 and Cofactors Npl4-Ufd1 Are Important for G1 Progression during Heat Stress by Maintaining Cell Wall Integrity in Saccharomyces cerevisiae

The ubiquitin-selective chaperone Cdc48, a member of the AAA (ATPase Associated with various cellular Activities) ATPase superfamily, is involved in many processes, including endoplasmic reticulum-associated degradation (ERAD), ubiquitin- and proteasome-mediated protein degradation, and mitosis. Although Cdc48 was originally isolated as a cell cycle mutant in the budding yeast Saccharomyces cerevisiae, its cell cycle functions have not been well appreciated. We found that temperature-sensitive cdc48-3 mutant is largely arrested at mitosis at 37°C, whereas the mutant is also delayed in G1 progression at 38.5°C. Reporter assays show that the promoter activity of G1 cyclin CLN1, but not CLN2, is reduced in cdc48-3 at 38.5°C. The cofactor npl4-1 and ufd1-2 mutants also exhibit G1 delay and reduced CLN1 promoter activity at 38.5°C, suggesting that Npl4-Ufd1 complex mediates the function of Cdc48 at G1. The G1 delay of cdc48-3 at 38.5°C is a consequence of cell wall defect that over-activates Mpk1, a MAPK family member important for cell wall integrity in response to stress conditions including heat shock. cdc48-3 is hypersensitive to cell wall perturbing agents and is synthetic-sick with mutations in the cell wall integrity signaling pathway. Our results suggest that the cell wall defect in cdc48-3 is exacerbated by heat shock, which sustains Mpk1 activity to block G1 progression. Thus, Cdc48-Npl4-Ufd1 is important for the maintenance of cell wall integrity in order for normal cell growth and division

Effects of Water and Nitrogen Addition on Species Turnover in Temperate Grasslands in Northern China

Global nitrogen (N) deposition and climate change have been identified as two of the most important causes of current plant diversity loss. However, temporal patterns of species turnover underlying diversity changes in response to changing precipitation regimes and atmospheric N deposition have received inadequate attention. We carried out a manipulation experiment in a steppe and an old-field in North China from 2005 to 2009, to test the hypothesis that water addition enhances plant species richness through increase in the rate of species gain and decrease in the rate of species loss, while N addition has opposite effects on species changes. Our results showed that water addition increased the rate of species gain in both the steppe and the old field but decreased the rates of species loss and turnover in the old field. In contrast, N addition increased the rates of species loss and turnover in the steppe but decreased the rate of species gain in the old field. The rate of species change was greater in the old field than in the steppe. Water interacted with N to affect species richness and species turnover, indicating that the impacts of N on semi-arid grasslands were largely mediated by water availability. The temporal stability of communities was negatively correlated with rates of species loss and turnover, suggesting that water addition might enhance, but N addition would reduce the compositional stability of grasslands. Experimental results support our initial hypothesis and demonstrate that water and N availabilities differed in the effects on rate of species change in the temperate grasslands, and these effects also depend on grassland types and/or land-use history. Species gain and loss together contribute to the dynamic change of species richness in semi-arid grasslands under future climate change

Histone deacetylase inhibitors: clinical implications for hematological malignancies

Histone modifications have widely been implicated in cancer development and progression and are potentially reversible by drug treatments. The N-terminal tails of each histone extend outward through the DNA strand containing amino acid residues modified by posttranslational acetylation, methylation, and phosphorylation. These modifications change the secondary structure of the histone protein tails in relation to the DNA strands, increasing the distance between DNA and histones, and thus allowing accessibility of transcription factors to gene promoter regions. A large number of HDAC inhibitors have been synthesized in the last few years, most being effective in vitro, inducing cancer cells differentiation or cell death. The majority of the inhibitors are in clinical trials, unlike the suberoylanilide hydroxamic acid, a pan-HDACi, and Romidepsin (FK 228), a class I-selective HDACi, which are only approved in the second line treatment of refractory, persistent or relapsed cutaneous T-cell lymphoma, and active in approximately 150 clinical trials, in monotherapy or in association. Preclinical studies investigated the use of these drugs in clinical practice, as single agents and in combination with chemotherapy, hypomethylating agents, proteasome inhibitors, and MTOR inhibitors, showing a significant effect mostly in hematological malignancies. The aim of this review is to focus on the biological features of these drugs, analyzing the possible mechanism(s) of action and outline an overview on the current use in the clinical practice

Temporally Regulated Traffic of HuR and Its Associated ARE-Containing mRNAs from the Chromatoid Body to Polysomes during Mouse Spermatogenesis

International audienceBACKGROUND: In mammals, a temporal disconnection between mRNA transcription and protein synthesis occurs during late steps of germ cell differentiation, in contrast to most somatic tissues where transcription and translation are closely linked. Indeed, during late stages of spermatogenesis, protein synthesis relies on the appropriate storage of translationally inactive mRNAs in transcriptionally silent spermatids. The factors and cellular compartments regulating mRNA storage and the timing of their translation are still poorly understood. The chromatoid body (CB), that shares components with the P. bodies found in somatic cells, has recently been proposed to be a site of mRNA processing. Here, we describe a new component of the CB, the RNA binding protein HuR, known in somatic cells to control the stability/translation of AU-rich containing mRNAs (ARE-mRNAs). METHODOLOGY/PRINCIPAL FINDINGS: Using a combination of cell imagery and sucrose gradient fractionation, we show that HuR localization is highly dynamic during spermatid differentiation. First, in early round spermatids, HuR colocalizes with the Mouse Vasa Homolog, MVH, a marker of the CB. As spermatids differentiate, HuR exits the CB and concomitantly associates with polysomes. Using computational analyses, we identified two testis ARE-containing mRNAs, Brd2 and GCNF that are bound by HuR and MVH. We show that these target ARE-mRNAs follow HuR trafficking, accumulating successively in the CB, where they are translationally silent, and in polysomes during spermatid differentiation. CONCLUSIONS/SIGNIFICANCE: Our results reveal a temporal regulation of HuR trafficking together with its target mRNAs from the CB to polysomes as spermatids differentiate. They strongly suggest that through the transport of ARE-mRNAs from the CB to polysomes, HuR controls the appropriate timing of ARE-mRNA translation. HuR might represent a major post-transcriptional regulator, by promoting mRNA storage and then translation, during male germ cell differentiation