A Novel DBL-Domain of the P. falciparum 332 Molecule Possibly Involved in Erythrocyte Adhesion

Plasmodium falciparum malaria is brought about by the asexual stages of the parasite residing in human red blood cells (RBC). Contact between the erythrocyte surface and the merozoite is the first step for successful invasion and proliferation of the parasite. A number of different pathways utilised by the parasite to adhere and invade the host RBC have been characterized, but the complete biology of this process remains elusive. We here report the identification of an open reading frame (ORF) representing a hitherto unknown second exon of the Pf332 gene that encodes a cysteine-rich polypeptide with a high degree of similarity to the Duffy-binding-like (DBL) domain of the erythrocyte-binding-ligand (EBL) family. The sequence of this DBL-domain is conserved and expressed in all parasite clones/strains investigated. In addition, the expression level of Pf332 correlates with proliferation efficiency of the parasites in vitro. Antibodies raised against the DBL-domain are able to reduce the invasion efficiency of different parasite clones/strains. Analysis of the DBL-domain revealed its ability to bind to uninfected human RBC, and moreover demonstrated association with the iRBC surface. Thus, Pf332 is a molecule with a potential role to support merozoite invasion. Due to the high level of conservation in sequence, the novel DBL-domain of Pf332 is of possible importance for development of novel anti-malaria drugs and vaccines

Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia

NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis

Lymphocyte activation induced by Trichinella spiralis infection reflected as spontaneous DNA synthesis in vitro.

Spleen cells from mice, infected with Trichinella spiralis, were cultured in micro and macrocultures without stimulatory agents. As controls, various polyclonal T and B cell activators were used. During the course of the infection the cells exhibited an increased spontaneous DNA synthesis compared to the cells from uninfected controls. It was also found that the relative proportion of theta and Ig-positive cells and macrophages was not significantly affected by the infection. To characterize the in vivo stimulated cells one week after infection various techniques were used. Autoradiography combined with immunofluorescence revealed that virtually all labelled cells were Ig-negative. Removal of macrophages by silica powder decreased the spontaneous DNA synthesis but not to the level of the controls. Spleen cells from infected nude mice did not show any increased spontaneous DNA synthesis, whereas the effluent cells obtained after separation on Ig-complexed columns still showed an enhanced spontaneous DNA synthesis. These results indicate that T. spiralis infection causes a macrophage dependent activation of T cells which in vitro is detectable as spontaneous DNA synthesis

Feeding freqency and parental division of Labour in the double-brooded great tit Parus major

We studied the relative contribution of each sex and total effort expended in feeding nestlings in the great tit Parus major in relation to artificially altered brood size. A recent model suggests that feeding frequency should reflect the optimal trade-off between parental and fledgling survival, the former being negatively, the latter positively, influenced by high feeding frequencies. In both sexes weight loss was linearly related to feeding frequency. Since fledgling survival increases with nestling weight, the conditions of this model are fulfilled. However, in contrast to the predictions of the model, the total feeding frequency for both sexes combined did not differ between control and enlarged broods, but was lower for reduced ones. This outcome was not the result of a physiologically related inability of the parents to increase their delivery rate. Instead, we suggest that parents with enlarged broods could not find sufficient amounts of prey large enough to be economically worth transporting to the nest. Differences in brood-provisioning rates between the sexes may arise because costs and benefits of feeding nestlings may differ. Females lost more weight than males during the nesting period, but maintained a relatively higher weight during the incubation period. The relationship between weight loss and feeding frequency was similar for both sexes. Male and female brood-feeding frequency was related to brood size in a similar way. This is discussed in light of the great tit's mating system and the fact that the great tit is facultatively double-brooded