Modulation of the activity of histone acetyltransferases by long chain alkylidenemalonates (LoCAMs)

A novel class of KAT modulators (long chain alkylidenemalonates, LoCAMs) has been identified. Variations of the alkyl chain length can change the activity profile from inhibition of both KAT3A/KAT2B (as derivative 2a) to the peculiar profile of pentadecylidenemalonate 1b, the first activator/inhibitor of histone acetyltransferases. Together with the powerful apoptotic effect (particularly notable if considering that anacardic acid and other KAT inhibitors are not cell permeable) appoint them as valuable biological tools to understand the mechanisms of lysine acetyltransferases.     

Effects of light deprivation on visual evoked potentials in migraine without aura

Background  

The mechanisms underlying the interictal habituation deficit of cortical visual evoked potentials (VEP) in migraine are not well understood. Abnormal long-term functional plasticity of the visual cortex may play a role and it can be assessed experimentally by light deprivation (LD).     

Exercise intensity and pacing strategy of a 5-km indoor race walk during a World Record attempt: a case study

The aim of this case study was to describe the physiological and regulatory processes, by means of heart rate (HR) monitoring and pacing strategy, in a top-level race walker (age: 32 years; height: 1.76 m; body mass: 62 kg; training volume: 130-150 km·wk) who was focused on the attainment of the 5-km indoor race walk (RW) World Record. The HRmean was 185 ± 14.9 b·min, with an HRmean/HRmax ratio of 0.96. Almost the whole race (91.8%) was performed to an intensity ≥90% of the HRmax; lower intensity work was negligible (8.1%). The race profile was a reverse J-shaped pacing curve; in fact, the athlete completed the first 1,000 m in the fastest time, slowing during the middle 3,000 m, and increasing the speed during the final 1,000 m of the race. Despite the attempt failed (the athlete performed only the 2009 World leading performance, 18 minutes 23 seconds 47 tenths), these data suggest that a more linear strain distribution for the entire performance would be optimal instead of a fast-start strategy, which leads to a drastic decrement of the walking velocity. Moreover, this study supports the use of HR monitoring combined with the regulation of the effort to understand the physiological and regulatory processes during an indoor RW event.     

Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat)

ITF2357 (givinostat) is a histone deacetylase inhibitor with antiinflammatory properties at low nanomolar concentrations. We report here a phase I safety and pharmacokinetics trial in healthy males administered 50, 100, 200, 400 or 600 mg orally. After 50 mg, mean maximal plasma concentrations reached 104 nmol/L 2 h after dosing, with a half-life of 6.9 h. After 100 mg, maximal concentration reached 199 nmol/L at 2.1 h with a half-life of 6.0 h. Repeat doses for 7 consecutive days of 50, 100 or 200 mg resulted in nearly the same kinetics. There were no serious adverse effects (AEs) and no organ toxicities. However, there was a dose-dependent but transient fall in platelets. After 7 daily doses of 50 or 100 mg, the mean decrease in platelets of 17 and 25% was not statistically significant and returned to baseline within 14 d. Blood removed from the subjects after oral dosing was cultured ex vivo with endotoxin, and the release of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-1Ra, interferon (IFN)-γ and IL-10 was determined. Maximal reduction in IL-1β, TNFα, IL-6 and IFNγ was observed 4 h after dosing but returned to baseline at 12 h. There was no significant reduction in IL-1Ra or IL-10. With daily dosing, the fall in cytokine production in blood cultures observed on day 7 was nearly the same as that of the first day. We conclude that dosing of 50 or 100 mg ITF2357 is safe in healthy humans and transiently but repeatedly reduces the production of proinflammatory cytokines without affecting production of antiinflammatory cytokines.     

Epicardial fat: from the biomolecular aspects to the clinical practice

Epicardial fat is the visceral fat depot of heart. It is a metabolically active organ with anatomical and functional contiguity to the myocardium. A dichotomous role has been attributed to the epicardial fat. Under physiological conditions, epicardial fat displays biochemical and thermogenic cardio-protective properties. Under pathological circumstances epicardial fat can locally affect the heart and coronary arteries through vasocrine or paracrine secretion of pro-inflammatory cytokines. Epicardial fat can be measured with imaging techniques. Epicardial fat thickness reflects intra-abdominal and myocardial fat and correlates with metabolic syndrome and coronary artery disease. Epicardial fat measurement may play a role in the stratification of the cardio-metabolic risk and serve as therapeutic target. Weight loss and anti-inflammatory drugs targeting the fat may modulate epicardial fat. Because epicardial and myocardial tissues share the same coronary arterial supply it is reasonable to hypothesize that improved local vascularisation may resume epicardial fat to its physiological role.     

A reference map of the membrane proteome of Enterococcus faecalis

Enterococcus faecalis is a gram-positive bacterium that is part of the indigenous microbiotica of humans and animals as well as an opportunistic pathogen. In this study, we have fractionated the membrane proteome of E. faecalis and identified many of its constituents by mass spectrometry. We present blue native-/SDS-PAGE reference maps that contain 102 proteins. These proteins are important for cellular homeostasis, virulence, and antibiotic intervention. Intriguingly, many proteins with no known function were also identified, indicating that there are substantial gaps in the knowledge of this organism's biology. On a more limited scale, we also provide insight into the composition of membrane protein complexes. This study is a first step toward elucidating the membrane proteome of E. faecalis, which is critical for a better understanding of how this bacterium interacts with a host and with the extracellular milieu.     

Acoustic communication at the water's edge: evolutionary insights from a mudskipper

Coupled behavioural observations and acoustical recordings of aggressive dyadic contests showed that the mudskipper Periophthalmodon septemradiatus communicates acoustically while out of water. An analysis of intraspecific variability showed that specific acoustic components may act as tags for individual recognition, further supporting the sounds' communicative value. A correlative analysis amongst acoustical properties and video-acoustical recordings in slow-motion supported first hypotheses on the emission mechanism. Acoustic transmission through the wet exposed substrate was also discussed. These observations were used to support an "exaptation hypothesis", i.e. the maintenance of key adaptations during the first stages of water-to-land vertebrate eco-evolutionary transitions (based on eco-evolutionary and palaeontological considerations), through a comparative bioacoustic analysis of aquatic and semiterrestrial gobiid taxa. In fact, a remarkable similarity was found between mudskipper vocalisations and those emitted by gobioids and other soniferous benthonic fishes.     

Characterizing associations and SNP-environment interactions for GWAS-identified prostate cancer risk markers--results from BPC3

Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10⁻²⁸). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade <8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined.     

Efficient detection of proteins retro-translocated from the ER to the cytosol by in vivo biotinylation

Retro-translocation from the ER to the cytosol of proteins within the secretory pathway takes place on misfolded molecules that are targeted for degradation by the cytosolically located 26S proteasome complex. Retro-translocation occurs also for other proteins (such as calreticulin) that, despite being synthesized and transported to the ER, are in part dislocated to the cytosol. We have taken advantage of the E. coli derived biotin-ligase (BirA) expressed in the cytosol of mammalian cells to specifically biotin-label in vivo proteins within the secretory pathway that undergo retro-translocation. We validated the method using four different proteins that are known to undergo retro-translocation upon different conditions: the human trans-membrane protein MHC class-I α chain (MHC-Iα), the Null Hong Kong mutant of the secretory α1 anti-trypsin (NHK-α1AT), the immunoglobulin heavy chain (HC) and the ER chaperone calreticulin (Crt). We observed specific mono-biotinylation of cytosolically dislocated molecules, resulting in a novel, reliable way of determining the extent of retro-translocation.     

Severe and persistent depletion of circulating plasmacytoid dendritic cells in patients with 2009 pandemic H1N1 infection

Background

Dysregulation of host immune responses plays a critical role in the pathogenesis of severe 2009 pandemic H1N1 infection. Whether H1N1 virus could escape innate immune defense in vivo remains to be investigated. The aim of this study was to evaluate the pattern of innate immune response during human 2009 H1N1 infection. We performed the enumeration of circulating myeloid dendritic cells (mDC) and plasmacytoid DC (pDC) in blood from patients with H1N1 pneumonia shortly after the onset of symptoms and during follow-up at different intervals of time. The analysis of CD4 and CD8 count, CD38 T-cell activation marker and serum cytokine/chemokine plasma levels was also done.

Methodology/Principal Findings

Blood samples were collected from 13 hospitalized patients with confirmed H1N1-related pneumonia at time of admission and at weeks 1, 4, and 16 of follow-up. 13 healthy donors were enrolled as controls. In the acute phase of the disease, H1N1-infected patients exhibited a significant depletion in both circulating pDC and mDC in conjunction with a decrease of CD4 and CD8 T cell count. In addition, we found plasmatic hyperproduction of IP-10 and RANTES, whereas increase in T-cell immune activation was found at all time points. When we assessed the changes in DC count over time, we observed a progressive normalization of mDC number. On the contrary, H1N1-infected patients did not achieve a complete recovery of pDC count as values remained lower than healthy controls even after 16 weeks of follow-up.

Conclusions

H1N1 disease is associated with a profound depletion of DC subsets. The persistence of pDC deficit for several weeks after disease recovery could be due to H1N1 virus itself or to a preexisting impairment of innate immunity.