Epigenetic repression of Wnt receptors in AD: a role for Sirtuin2-induced H4K16ac deacetylation of Frizzled1 and Frizzled7 promoters

Growing evidence supports a role for deficient Wnt signalling in Alzheimer’s disease (AD). First, the Wnt antagonist DKK1 is elevated in AD brains and is required for amyloid-β-induced synapse loss. Second, LRP6 Wnt co-receptor is required for synapse integrity and three variants of this receptor are linked to late-onset AD. However, the expression/role of other Wnt signalling components remain poorly explored in AD. Wnt receptors Frizzled1 (Fzd1), Fzd5, Fzd7 and Fzd9 are of interest due to their role in synapse formation/plasticity. Our analyses showed reduced FZD1 and FZD7 mRNA levels in the hippocampus of human early AD stages and in the hAPPNLGF/NLGF mouse model. This transcriptional downregulation was accompanied by reduced levels of the pro-transcriptional histone mark H4K16ac and a concomitant increase of its deacetylase Sirt2 at Fzd1 and Fzd7 promoters in AD. In vitro and in vivo inhibition of Sirt2 rescued Fzd1 and Fzd7 mRNA expression and H4K16ac levels at their promoters. In addition, we showed that Sirt2 recruitment to Fzd1 and Fzd7 promoters is dependent on FoxO1 activity in AD, thus acting as a co-repressor. Finally, we found reduced levels of SIRT2 inhibitory phosphorylation in nuclear samples from human early AD stages with a concomitant increase in the SIRT2 phosphatase PP2C. This results in hyperactive nuclear Sirt2 and favours Fzd1 and Fzd7 repression in AD. Collectively, our findings define a novel role for nuclear hyperactivated SIRT2 in repressing Fzd1 and Fzd7 expression via H4K16ac deacetylation in AD. We propose SIRT2 as an attractive target to ameliorate AD pathology

Distal posterior tibial artery perforator flaps for the management of calcaneal and Achilles tendon injuries in diabetic and non-diabetic patients

Management of Achilles tendon and heel area defects is a common challenge for the reconstructive surgeon due to the lack of soft tissue availability in that region. In this article, we present our experience in covering these defects by using the distal perforator propeller flaps based on the posterior tibial artery. Perforator flaps are based on cutaneous, small diameter vessels that originate from a main pedicle and perforate the fascia or muscle to reach the skin. Their development has followed the understanding of the blood supply from a source artery to the skin. Six patients (five males and one female) underwent reconstruction by using the posterior tibial artery distal perforator flap for covering defects in the distal Achilles tendon region in patients with and without diabetes mellitus. Postoperative complications included a hypertrophic scar formation in one patient, partial marginal flap necrosis in another patient, and a wound infection in a third patient. All wounds were eventually healed by the last postoperative visit. In conclusion, perforator flaps based on the distal posterior tibial artery may be a reliable option for the coverage of small to moderate size defects of the Achilles tendon and heel area regions

Paradox of low field enhancement factor for field emission nanodiodes in relation to quantum screening effects

We put forward the quantum screening effect in field emission [FE] nanodiodes, explaining relatively low field enhancement factors due to the increased potential barrier that impedes the electron Fowler-Nordheim tunneling, which is usually observed in nanoscale FE experiments. We illustratively show this effect from the energy band diagram and experimentally verify it by performing the nanomanipulation FE measurement for a single P-silicon nanotip emitter (Φ = 4.94eV), with a scanning tungsten-probe anode (work function, Φ = 4.5eV) that constitutes a 75-nm vacuum nanogap. A macroscopic FE measurement for the arrays of emitters with a 17-μm vacuum microgap was also performed for a fair comparison

Identification of a novel zinc metalloprotease through a global analysis of clostridium difficile extracellular proteins

Clostridium difficile is a major cause of infectious diarrhea worldwide. Although the cell surface proteins are recognized to be important in clostridial pathogenesis, biological functions of only a few are known. Also, apart from the toxins, proteins exported by C. difficile into the extracellular milieu have been poorly studied. In order to identify novel extracellular factors of C. difficile, we analyzed bacterial culture supernatants prepared from clinical isolates, 630 and R20291, using liquid chromatography-tandem mass spectrometry. The majority of the proteins identified were non-canonical extracellular proteins. These could be largely classified into proteins associated to the cell wall (including CWPs and extracellular hydrolases), transporters and flagellar proteins. Seven unknown hypothetical proteins were also identified. One of these proteins, CD630_28300, shared sequence similarity with the anthrax lethal factor, a known zinc metallopeptidase. We demonstrated that CD630_28300 (named Zmp1) binds zinc and is able to cleave fibronectin and fibrinogen in vitro in a zinc-dependent manner. Using site-directed mutagenesis, we identified residues important in zinc binding and enzymatic activity. Furthermore, we demonstrated that Zmp1 destabilizes the fibronectin network produced by human fibroblasts. Thus, by analyzing the exoproteome of C. difficile, we identified a novel extracellular metalloprotease that may be important in key steps of clostridial pathogenesis

Progression from new methicillin-resistant Staphylococcus aureus colonisation to infection: An observational study in a hospital cohort

10.1186/1471-2334-13-491BMC Infectious Diseases131-BIDM

Non-travel related Hepatitis E virus genotype 3 infections in the Netherlands; A case series 2004 – 2006

<p>Abstract</p> <p>Background</p> <p>Human hepatitis E virus (HEV) infections are considered an emerging disease in industrialized countries. In the Netherlands, Hepatitis E virus (HEV) infections have been associated with travel to high-endemic countries. Non-travel related HEV of genotype 3 has been diagnosed occasionally since 2000. A high homology of HEV from humans and pigs suggests zoonotic transmission but direct molecular and epidemiological links have yet to be established. We conducted a descriptive case series to generate hypotheses about possible risk factors for non-travel related HEV infections and to map the genetic diversity of HEV.</p> <p>Methods</p> <p>A case was defined as a person with HEV infection laboratory confirmed (positive HEV RT-PCR and/or HEV IgM) after 1 January 2004, without travel to a high-endemic country three months prior to onset of illness. For virus identification 148 bp of ORF2 was sequenced and compared with HEV from humans and pigs. We interviewed cases face to face using a structured questionnaire and collected information on clinical and medical history, food preferences, animal and water contact.</p> <p>Results</p> <p>We interviewed 19 cases; 17 were male, median age 50 years (25–84 y), 12 lived in the North-East of the Netherlands and 11 had preexisting disease. Most common symptoms were dark urine (n = 16) and icterus (n = 15). Sixteen ate pork ≥ once/week and six owned dogs. Two cases had received blood transfusions in the incubation period. Seventeen cases were viremic (genotype 3 HEV), two had identical HEV sequences but no identified relation. For one case, HEV with identical sequence was identified from serum and surface water nearby his home.</p> <p>Conclusion</p> <p>The results show that the modes of transmission of genotype-3 HEV infections in the Netherlands remains to be resolved and that host susceptibility may play an important role in development of disease.</p