Multiple sclerosis: peripheral mononuclear cells inhibit <i>Plasmodium falciparum</i> growth and are activated by parasite antigens

The human genome has been subjected to selective pressures to resist to infectious agents in spite of a heavy segregational load. With this regard, thalassaemia and glucose-6-phosphate dehydrogenase deficiency have been considered an efficient genetic protection against P. falciparum malaria in Sardinia, insular Italy. In this island, some multiple sclerosis (MS)-associated HLA haplotypes have the highest odds ratios in the same highestrate malarious areas of the island. Moreover, tumor necrosis factor (TNF) polymorphisms epidemiologically associated with both MS and malaria are ten-fold more frequent amongst Sardinians compared to other populations worldwide4. A possible association between MS and malaria in this island was never analysed experimentally. We studied the immunological response of mononuclear cells to P. falciparum and the killing effect of macrophages on parasites in Sardinian MS patients and in matched healthy controls (HC)

Specific tagging of the egress-related osmiophilic bodies in the gametocytes of Plasmodium falciparum

<p>Abstract</p> <p>Background</p> <p>Gametocytes, the blood stages responsible for <it>Plasmodium falciparum </it>transmission, contain electron dense organelles, traditionally named osmiophilic bodies, that are believed to be involved in gamete egress from the host cell. In order to provide novel tools in the cellular and molecular studies of osmiophilic body biology, a <it>P. falciparum </it>transgenic line in which these organelles are specifically marked by a reporter protein was produced and characterized.</p> <p>Methodology</p> <p>A <it>P. falciparum </it>transgenic line expressing an 80-residue N-terminal fragment of the osmiophilic body protein Pfg377 fused to the reporter protein DsRed, under the control of <it>pfg377 </it>upstream and downstream regulatory regions, was produced.</p> <p>Results</p> <p>The transgenic fusion protein is expressed at the appropriate time and stage of sexual differentiation and is trafficked to osmiophilic bodies as the endogenous Pfg377 protein. These results indicate that a relatively small N-terminal portion of Pfg377 is sufficient to target the DsRed reporter to the gametocyte osmiophilic bodies.</p> <p>Conclusions</p> <p>This is the first identification of a <it>P. falciparum </it>aminoacid sequence able to mediate trafficking to such organelles. To fluorescently tag such poorly characterized organelles opens novel avenues in cellular and imaging studies on their biogenesis and on their role in gamete egress.</p

The Outcome of Cholangitis After Percutaneous Biliary Drainage in Neoplastic Jaundice

The purpose of this paper is to evaluate factors affecting the outcome of cholangitis after PTBD in jaundiced cancer patients. Twenty nine patients with neoplastic jaundice (male/female ratio 13/16, median age 55 years) with full clinical data, were treated by PTBD and developed cholangitis at a median of 9 days later. Four patients (14%) died of biliary sepsis a median of one month after PTBD while the other 25 survived a median of 6 months, with one week median duration of cholangitis. The probability of the cholangitis resolving was analyzed by time to resolution and it was found that 50% and 100% of the recoveries occurred 5 and 9 months respectively from the onset of the complication

Antiplasmodial Effects of a few Selected Natural Flavonoids and their Modulation of Artemisinin Activity

The direct antiplasmodial effects of five structurally-related flavonoids, namely quercetin, rutin, eriodictyol, eriodictyolchalcone and catechin, were analyzed in vitro on P. falciparum. Notably, all these flavonoids, with the only exception of rutin, caused relevant inhibition of P. falciparum growth when given at 1 mM concentration. In addition, they were found to affect greatly the potent antiplasmodial activity of artemisinin, leading to significant additive and even synergistic effects. In particular, quercetin induced a pronounced synergistic effect. The observed synergisms might be conveniently exploited to design new and/or more effective combination therapies

Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis

Suppressor of Fused (SuFu), a tumour suppressor mutated in medulloblastoma, is a central player of Hh signalling, a pathway crucial for development and deregulated in cancer. Although the control of Gli transcription factors by SuFu is critical in Hh signalling, our understanding of the mechanism regulating this key event remains limited. Here, we show that the Itch/β-arrestin2 complex binds SuFu and induces its Lys63-linked polyubiquitylation without affecting its stability. This process increases the association of SuFu with Gli3, promoting the conversion of Gli3 into a repressor, which keeps Hh signalling off. Activation of Hh signalling antagonises the Itch-dependent polyubiquitylation of SuFu. Notably, different SuFu mutations occurring in medulloblastoma patients are insensitive to Itch activity, thus leading to deregulated Hh signalling and enhancing medulloblastoma cell growth. Our findings uncover mechanisms controlling the tumour suppressive functions of SuFu and reveal that their alterations are implicated in medulloblastoma tumorigenesis

Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis

Suppressor of Fused (SuFu), a tumour suppressor mutated in medulloblastoma, is a central player of Hh signalling, a pathway crucial for development and deregulated in cancer. Although the control of Gli transcription factors by SuFu is critical in Hh signalling, our understanding of the mechanism regulating this key event remains limited. Here, we show that the Itch/β-arrestin2 complex binds SuFu and induces its Lys63-linked polyubiquitylation without affecting its stability. This process increases the association of SuFu with Gli3, promoting the conversion of Gli3 into a repressor, which keeps Hh signalling off. Activation of Hh signalling antagonises the Itch-dependent polyubiquitylation of SuFu. Notably, different SuFu mutations occurring in medulloblastoma patients are insensitive to Itch activity, thus leading to deregulated Hh signalling and enhancing medulloblastoma cell growth. Our findings uncover mechanisms controlling the tumour suppressive functions of SuFu and reveal that their alterations are implicated in medulloblastoma tumorigenesis

Genetic profiling of autoinflammatory disorders in patients with periodic fever: a prospective study

Periodic fever syndromes (PFS) are an emerging group of autoinflammatory disorders. Clinical overlap exists and multiple genetic analyses may be needed to assist diagnosis. We evaluated the diagnostic value of a 5-gene sequencing panel (5GP) in patients with undiagnosed PFS