C11ORF24 Is a Novel Type I Membrane Protein That Cycles between the Golgi Apparatus and the Plasma Membrane in Rab6-Positive Vesicles

The Golgi apparatus is an intracellular compartment necessary for post-translational modification, sorting and transport of proteins. It plays a key role in mitotic entry through the Golgi mitotic checkpoint. In order to identify new proteins involved in the Golgi mitotic checkpoint, we combine the results of a knockdown screen for mitotic phenotypes and a localization screen. Using this approach, we identify a new Golgi protein C11ORF24 (NP_071733.1). We show that C11ORF24 has a signal peptide at the N-terminus and a transmembrane domain in the C-terminal region. C11ORF24 is localized on the Golgi apparatus and on the trans-Golgi network. A large part of the protein is present in the lumen of the Golgi apparatus whereas only a short tail extends into the cytosol. This cytosolic tail is well conserved in evolution. By FRAP experiments we show that the dynamics of C11ORF24 in the Golgi membrane are coherent with the presence of a transmembrane domain in the protein. C11ORF24 is not only present on the Golgi apparatus but also cycles to the plasma membrane via endosomes in a pH sensitive manner. Moreover, via video-microscopy studies we show that C11ORF24 is found on transport intermediates and is colocalized with the small GTPase RAB6, a GTPase involved in anterograde transport from the Golgi to the plasma membrane. Knocking down C11ORF24 does not lead to a mitotic phenotype or an intracellular transport defect in our hands. All together, these data suggest that C11ORF24 is present on the Golgi apparatus, transported to the plasma membrane and cycles back through the endosomes by way of RAB6 positive carriers.     

The prion protein family

Although the pivotal implication of the host-encoded Prion protein, PrP, in the neuropathology of transmissible spongiform encephalopathy is known for decades, its biological role remains mostly elusive. Genetic inactivation is one way to assess such issue but, so far, PrP-knockout mice did not help much. However, recent reports involving (1) further studies of these mice during embryogenesis, (2) knockdown experiments in Zebrafish and (3) knockdown of Shadoo, a protein with PrP-like functional domains, in PrP-knockout mice, all suggested a role of the Prion protein family in early embryogenesis. This view is challenged by the recent report that PrP/Shadoo knockout mice are healthy and fertile. Although puzzling, these apparently contradictory data may on the contrary help at deciphering the Prion protein family role through focusing scientific attention outside the central nervous system and by helping the identification of other loci involved in the genetic robustness associated with PrP.     

Differential Response to Water Balance and Bunch Load Generates Diversity of Bunch Production Profiles Among Oil Palm Crosses (Elaeis guineensis)

Oil palm (Elaeis guineensis Jacq.) produces bunches throughout the year, following annual cycles marked by a peak season, with genetic diversity regarding the regularity of the annual profile of bunch production. The aim of this study was to understand this diversity among a set of oil palm crosses. We hypothesized that this diversity originated from differential responses to water balance and bunch load. Seven crosses with different production cycles were studied during 6 years in Benin, where dry seasons are marked. Phenological stages of phytomer development were recorded from leaf appearance to bunch harvest. Inequality in the distribution over the months of the year of phytomers at each stage was quantified using the Gini coefficient. We found that annual variations in the rate of early abortions, sex ratio, time between leaf opening and appearance of female inflorescence (AFI) and time between AFI and flowering strongly contributed to the diversity in production profile among crosses. To a lesser extent, annual variations in the time of bunch maturation also generated diversity in the production profile. Sex ratio was positively correlated with water balance and negatively with bunch load when leaves were around axil number -25 (approximately 29 months before harvest). Early abortions were positively correlated with bunch load when leaves were at axil number 10 (approximately 9 months before harvest). Correlations varied among crosses, indicating differential responses of crosses to variations in water balance and bunch load, which eventually created significant diversity among crosses regarding the regularity of bunch production profiles.     

Characterization of a surrogate murine antibody to model anti-human CD3 therapies

Fc-modified anti-human CD3ε monoclonal antibodies (mAbs) are in clinical development for the treatment of autoimmune diseases. These next generation mAbs have completed clinical trials in patients with type-1 diabetes and inflammatory bowel disease demonstrating a narrow therapeutic window. Lowered doses are ineffective, yet higher pharmacologically-active doses cause an undesirable level of adverse events. Thus, there is a critical need for a return to bench research to explore ways of improving clinical outcomes. Indeed, we recently reported that a short course of treatment affords synergy, providing long-term disease amelioration when combining anti-mouse CD3 and anti-mouse tumor necrosis factor mAbs in experimental arthritis. Such strategies may widen the window between risk and benefit; however, to more accurately assess experimentally the biology and pharmacology, reagents that mimic the current development candidates were required. Consequently, we engineered an Fc-modified anti-mouse CD3ε mAb, 2C11-Novi. Here, we report the functional characterization of 2C11-Novi demonstrating that it does not bind FcγR in vitro and elicits little cytokine release in vivo, while maintaining classical pharmacodynamic effects (CD3-TCR downregulation and T cell killing). Furthermore, we observed that oral administration of 2C11-Novi ameliorated progression of remitting-relapsing experimental autoimmune encephalitis in mice, significantly reducing the primary acute and subsequent relapse phase of the disease. With innovative approaches validated in two experimental models of human disease, 2C11-Novi represents a meaningful tool to conduct further mechanistic studies aiming at exploiting the immunoregulatory properties of Fc-modified anti-CD3 therapies via combination therapy using parenteral or oral routes of administration.     

Mixing Nulliparous and Multiparous Women in Randomised Controlled Trials of Preeclampsia Prevention Is Debatable: Evidence from a Systematic Review

Background

Nulliparity is a major risk factor of preeclampsia investigated in numerous trials of its prevention.

Objective

We aimed to assess whether these trials considered nulliparity in subject selection or analysis of results.

Search Strategy

01 April 2013 search of MEDLINE via PubMed, EMBASE and the Cochrane Library. 01 April 2013 search of trials registered in Clinicaltrials.gov.

Selection Criteria

Randomised controlled trials and metaanalyses of preeclampsia prevention with no restriction to period of publication or language. Metaanalyses were selected to fully identify relevant trials.

Data Collection and Analysis

One reader appraised each selected article/registered protocol using a pretested, standardized data abstraction form developed in a pilot test. For each article, he recorded whether both nulliparous and multiparous were included and, in case of mixed populations, whether randomisation was stratified, and whether subgroup analyses had been reported. For registered protocols, he only assessed whether it was planned to include mixed populations.

Main Results

88 randomised controlled trials were identified, representing 83,396 included women. In 58 of the 88 articles identified (65.9%), preeclampsia was the primary outcome. In 31 of these (53.4%), the investigation combined nulliparous and multiparous women; only two reports in 31 (6.5%) stated that randomisation was stratified on parity and only four (12.9%) described a subgroup analysis by parity. Of the 30 registered trials, 20 (66.6%) planned to include both nulliparous and multiparous women.

Conclusion

Parity is largely ignored in randomised controlled trials of preeclampsia prevention, which raises difficulties in interpreting the results.     

Multiple Sclerosis in the Mount Etna Region: Possible Role of Volcanogenic Trace Elements

Background

Trace elements have been hypothesised to be involved in the pathogenesis of Multiple Sclerosis and volcanic degassing is the major natural sources of trace elements. Both incidence of Multiple Sclerosis in Catania and volcanic activity of Mount Etna have been significantly increased during the last 30 years. Due to prevailing trade winds direction, volcanic gases from Etna summit craters are mostly blown towards the eastern and southern sectors of the volcano.

Objective

To evaluate the possible association between Multiple Sclerosis and exposure to volcanogenic trace elements.

Methods

We evaluated prevalence and incidence of Multiple Sclerosis in four communities (47,234 inhabitants) located in the eastern flank and in two communities (52,210 inhabitants) located in the western flank of Mount Etna, respectively the most and least exposed area to crater gas emissions.

Results

A higher prevalence was found in the population of the eastern flank compared to the population of the western one (137.6/100,000 versus 94.3/100,000; p-value 0.04). We found a borderline significantly higher incidence risk during the incidence study period (1980–2009) in the population of the eastern flank 4.6/100,000 (95% CI 3.1–5.9), compared with the western population 3.2/100,000 (95% CI 2.4–4.2) with a RR of 1.41 (95% CI 0.97–2.05; p-value 0.06). Incidence risks have increased over the time in both populations reaching a peak of 6.4/100,000 in the eastern flank and of 4.4/100.000 in the western flank during 2000–2009.

Conclusion

We found a higher prevalence and incidence of Multiple Sclerosis among populations living in the eastern flank of Mount Etna. According to our data a possible role of TE cannot be ruled out as possible co-factor in the MS pathogenesis. However larger epidemiological study are needed to confirm this hypothesis.     

Are Frontal Cognitive and Atrophy Patterns Different in PSP and bvFTD? A Comparative Neuropsychological and VBM Study

Progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration (FTD) are two clinicohistological entities that share a severe prefrontal syndrome. To what extent do the cognitive syndrome and the location of the underlying brain atrophy unify or segregate these entities? Here, we examined the clinical and radiological patterns of frontal involvement and the neural bases of the cognitive dysfunctions observed in the Richardson form of PSP and the behavioral variant of FTD (bvFTD). The cognitive profile and grey and white matter volume of PSP (n = 19) and bvFTD (n = 16) patients and control participants (n = 18) were compared using a standard battery of neuropsychological tests and voxel-based morphometry (VBM), respectively. Analyses of correlations between neuropsychological and morphometric data were additionally performed. The severity and qualitative pattern of cognitive dysfunction was globally similar between the two patient groups. Grey matter volume was decreased in widespread frontal areas and in the temporal uncus in bvFTD, while it was decreased in the frontal and temporal lobes as well as in the thalamus in PSP. We also found an unexpected involvement of the frontal rectal gyrus in PSP patients compared to controls. Correlation analyses yielded different results in the two groups, with no area showing significant correlations in PSP patients, while several frontal and some temporal areas did so in bvFTD patients. In spite of minor neuropsychological and morphological differences, this study shows that the patterns of cognitive dysfunction and atrophy are very similar in PSP and bvFTD. However, executive dysfunction in these diseases may stem from partially divergent cortical and subcortical neural circuits.     

Expansion in CD39+ CD4+ Immunoregulatory T Cells and Rarity of Th17 Cells in HTLV-1 Infected Patients Is Associated with Neurological Complications

HTLV-1 infection is associated with several inflammatory disorders, including the neurodegenerative condition HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is unclear why a minority of infected subjects develops HAM/TSP. CD4⁺ T cells are the main target of infection and play a pivotal role in regulating immunity to HTLV and are hypothesized to participate in the pathogenesis of HAM/TSP. The CD39 ectonucleotidase receptor is expressed on CD4⁺ T cells and based on co-expression with CD25, marks T cells with distinct regulatory (CD39⁺CD25⁺) and effector (CD39⁺CD25⁻) function. Here, we investigated the expression of CD39 on CD4⁺ T cells from a cohort of HAM/TSP patients, HTLV-1 asymptomatic carriers (AC), and matched uninfected controls. The frequency of CD39⁺ CD4⁺ T cells was increased in HTLV-1 infected patients, regardless of clinical status. More importantly, the proportion of the immunostimulatory CD39⁺CD25⁻ CD4⁺ T-cell subset was significantly elevated in HAM/TSP patients as compared to AC and phenotypically had lower levels of the immunoinhibitory receptor, PD-1. We saw no difference in the frequency of CD39⁺CD25⁺ regulatory (Treg) cells between AC and HAM/TSP patients. However, these cells transition from being anergic to displaying a polyfunctional cytokine response following HTLV-1 infection. CD39⁻CD25⁺ T cell subsets predominantly secreted the inflammatory cytokine IL-17. We found that HAM/TSP patients had significantly fewer numbers of IL-17 secreting CD4⁺ T cells compared to uninfected controls. Taken together, we show that the expression of CD39 is upregulated on CD4⁺ T cells HAM/TSP patients. This upregulation may play a role in the development of the proinflammatory milieu through pathways both distinct and separate among the different CD39 T cell subsets. CD39 upregulation may therefore serve as a surrogate diagnostic marker of progression and could potentially be a target for interventions to reduce the development of HAM/TSP.