A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects

Mammals have three HP1 protein isotypes HP1β (CBX1), HP1γ (CBX3) and HP1α (CBX5) that are encoded by the corresponding genes Cbx1, Cbx3 and Cbx5. Recent work has shown that reduction of CBX3 protein in homozygotes for a hypomorphic allele (Cbx3 hypo) causes a severe postnatal mortality with around 99% of the homozygotes dying before weaning. It is not known what the causes of the postnatal mortality are. Here we show that Cbx3 hypo/hypo conceptuses are significantly reduced in size and the placentas exhibit a haplo-insufficiency. Late gestation Cbx3 hypo/hypo placentas have reduced mRNA transcripts for genes involved in growth regulation, amino acid and glucose transport. Blood vessels within the Cbx3 hypo/hypo placental labyrinth are narrower than wild-type. Newborn Cbx3 hypo/hypo pups are hypoglycemic, the livers are depleted of glycogen reserves and there is almost complete loss of stored lipid in brown adipose tissue (BAT). There is a 10-fold reduction in expression of the BAT-specific Ucp1 gene, whose product is responsible for non-shivering themogenesis. We suggest that it is the small size of the Cbx3 hypo/hypo neonates, a likely consequence of placental growth and transport defects, combined with a possible inability to thermoregulate that causes the severe postnatal mortality

Preventing Phosphorylation of Sterol Regulatory Element-Binding Protein 1a by MAP-Kinases Protects Mice from Fatty Liver and Visceral Obesity

The transcription factor sterol regulatory element binding protein (SREBP)-1a plays a pivotal role in lipid metabolism. Using the SREBP-1a expressing human hepatoma cell line HepG2 we have shown previously that human SREBP-1a is phosphorylated at serine 117 by ERK-mitogen-activated protein kinases (MAPK). Using a combination of cell biology and protein chemistry approach we show that SREBP-1a is also target of other MAPK-families, i.e. c-JUN N-terminal protein kinases (JNK) or p38 stress activated MAP kinases. Serine 117 is also the major phosphorylation site in SREBP-1a for JNK. In contrast to that the major phosphorylation sites of p38 MAPK family are serine 63 and threonine 426. Functional analyses reveal that phosphorylation of SREBP-1a does not alter protein/DNA interaction. The identified phosphorylation sites are specific for both kinase families also in cellular context. To provide direct evidence that phosphorylation of SREBP-1a is a regulatory principle of biological and clinical relevance, we generated transgenic mice expressing mature transcriptionally active N-terminal domain of human SREBP–1a variant lacking all identified phosphorylaton sites designed as alb-SREBP-1aΔP and wild type SREBP-1a designed as alb-SREBP-1a liver specific under control of the albumin promoter and a liver specific enhancer. In contrast to alb-SREBP–1a mice the phosphorylation–deficient mice develop no enlarged fatty livers under normocaloric conditions. Phenotypical examination reveales a massive accumulation of adipose tissue in alb-SREBP-1a but not in the phosphorylation deficient alb-SREBP-1aΔP mice. Moreover, preventing phosphorylation of SREBP-1a protects mice also from dyslipidemia. In conclusion, phosphorylation of SREBP-1a by ERK, JNK and p38 MAPK-families resembles a biological principle and plays a significant role, in vivo

Identification of restriction endonuclease with potential ability to cleave the HSV-2 genome: Inherent potential for biosynthetic versus live recombinant microbicides

<p>Abstract</p> <p>Background</p> <p>Herpes Simplex virus types 1 and 2 are enveloped viruses with a linear dsDNA genome of ~120–200 kb. Genital infection with HSV-2 has been denoted as a major risk factor for acquisition and transmission of HIV-1. Developing biomedical strategies for HSV-2 prevention is thus a central strategy in reducing global HIV-1 prevalence. This paper details the protocol for the isolation of restriction endunucleases (REases) with potent activity against the HSV-2 genome and models two biomedical interventions for preventing HSV-2.</p> <p>Methods and Results</p> <p>Using the whole genome of HSV-2, 289 REases and the bioinformatics software Webcutter2; we searched for potential recognition sites by way of genome wide palindromics. REase application in HSV-2 biomedical therapy was modeled concomitantly. Of the 289 enzymes analyzed; 77(26.6%) had potential to cleave the HSV-2 genome in > 100 but < 400 sites; 69(23.9%) in > 400 but < 700 sites; and the 9(3.1%) enzymes: BmyI, Bsp1286I, Bst2UI, BstNI, BstOI, EcoRII, HgaI, MvaI, and SduI cleaved in more than 700 sites. But for the 4: PacI, PmeI, SmiI, SwaI that had no sign of activity on HSV-2 genomic DNA, all 130(45%) other enzymes cleaved < 100 times. In silico palindromics has a PPV of 99.5% for in situ REase activity (2) Two models detailing how the REase EcoRII may be applied in developing interventions against HSV-2 are presented: a nanoparticle for microbicide development and a "recombinant lactobacillus" expressing cell wall anchored receptor (truncated nectin-1) for HSV-2 plus EcoRII.</p> <p>Conclusion</p> <p>Viral genome slicing by way of these bacterially- derived R-M enzymatic peptides may have therapeutic potential in HSV-2 infection; a cofactor for HIV-1 acquisition and transmission.</p

Natural Language Processing in Serious Games: A state of the art

In the last decades, Natural Language Processing (NLP) has obtained a high level of success. Interactions between NLP and Serious Games have started and some of them already include NLP techniques. The objectives of this paper are twofold: on the one hand, providing a simple framework to enable analysis of potential uses of NLP in Serious Games and, on the other hand, applying the NLP framework to existing Serious Games and giving an overview of the use of NLP in pedagogical Serious Games. In this paper we present 11 serious games exploiting NLP techniques. We present them systematically, according to the following structure:  first, we highlight possible uses of NLP techniques in Serious Games, second, we describe the type of NLP implemented in the each specific Serious Game and, third, we provide a link to possible purposes of use for the different actors interacting in the Serious Game

Accès palustres simples en zone de haut niveau de résistance à la chloroquine : 2. Evaluation de schémas thérapeutiques de première intention

Les auteurs étudient l'efficacité comparée de la chloroquine et de l'amodiaquine à la posologie de 35 mg/kg en trois jours, dans le cadre du traitement de l'accès palustre simple à #P. falciparum$ en zone à haut niveau de résistance. 236 sujets présentant un accès palustre sont inclus dans l'étude. 38 % avaient déjà utilisé des antipaludéens en ambulatoire. L'augmentation des posologies par rapport à celles préconisées par l'OMS (25 mg/kg) n'améliore pas l'efficacité thérapeutique de la chloroquine (50 % d'échec), contrairement à l'amodiaquine (4 % d'échec). L'efficacité thérapeutique de l'amodiaquine incite donc les auteurs à en recommander l'emploi dans les dispensaires. (Résumé d'auteur

Accès palustres simples en zone de haut niveau de résistance à la chloroquine : 3. Emploi de traitements de deuxième intention, par voie orale

Cette étude évalue l'efficacité des thérapeutiques de deuxième intention dans le traitement de l'accès palustre simple, à #P. falciparum$, en zone de haut niveau de résistance. Aucun échec thérapeutique n'a été observé avec les associations sulfadoxine-pyriméthamine (Fansidar) et méfloquine-sulfadoxine-pyriméthamine (Fansimef). La quinine entraîne elle 8 % d'échecs. Les auteurs discutent de la place de ces thérapeutiques dans le traitement. (Résumé d'auteur

Macrophage-specific apoE gene repair reduces diet-induced hyperlipidemia and atherosclerosis in hypomorphic apoE mice

Background: Apolipoprotein (apo) E is best known for its ability to lower plasma cholesterol and protect against atherosclerosis. Although the liver is the major source of plasma apoE, extra-hepatic sources of apoE, including from macrophages, account fo