Live imaging of <Emphasis Type="Italic">Drosophila</Emphasis>gonad formation reveals roles for Six4 in regulating germline and somatic cell migration

Background  

Movement of cells, either as amoeboid individuals or in organised groups, is a key feature of organ formation. Both modes of migration occur during Drosophila embryonic gonad development, which therefore provides a paradigm for understanding the contribution of these processes to organ morphogenesis. Gonads of Drosophila are formed from three distinct cell types: primordial germ cells (PGCs), somatic gonadal precursors (SGPs), and in males, male-specific somatic gonadal precursors (msSGPs). These originate in distinct locations and migrate to associate in two intermingled clusters which then compact to form the spherical primitive gonads. PGC movements are well studied, but much less is known of the migratory events and other interactions undergone by their somatic partners. These appear to move in organised groups like, for example, lateral line cells in zebra fish or Drosophila ovarian border cells.     

Differential responsiveness to immunoablative therapy in refractory rheumatoid arthritis is associated with level and avidity of anti-cyclic citrullinated protein autoantibodies: a case study

In order to identify pathogenic correlates of refractory rheumatoid arthritis (RA), antibodies against anti-cyclic citrullinated protein (ACPAs) were investigated in RA patients in whom the dysregulated immune system had been ablated by high-dose chemotherapy (HDC) and autologous haematopoietic stem cell transplantation (HSCT). Six patients with refractory RA were extensively characterized in terms of levels of total immunoglobulins, RA-specific autoantibodies (ACPAs and rheumatoid factor) and antibodies against rubella, tetanus toxoid (TT) and phosphorylcholine before and after HDC plus HSCT. Additionally, the avidity of ACPAs was measured before and after treatment and compared with the avidity of TT antibodies following repeated immunizations. Synovial biopsies were obtained by arthroscopy before HDC plus HSCT, and analyzed by immunohistochemistry. In the three patients with clinically long-lasting responses to HDC plus HSCT (median 423 days), significant reductions in ACPA-IgG levels after therapy were observed (median level dropped from 215 to 34 arbitrary units/ml; P = 0.05). In contrast, stable ACPA-IgG levels were observed in three patients who relapsed shortly after HDC plus HSCT (median of 67 days). Clinical responders had ACPA-IgG of lower avidity (r = 0.75; P = 0.08) and higher degree of inflammation histologically (r = 0.73; P = 0.09). Relapse (after 38 to 530 days) in all patients was preceded by rising levels of low avidity ACPA-IgG (after 30 to 388 days), in contrast to the stable titres of high avidity TT antibodies. In conclusion, humoral autoimmune responses were differentially modulated by immunoablative therapy in patients with synovial inflammation and low avidity ACPA-IgG autoantibodies as compared with patients with high levels of high avidity ACPA-IgG. The distinct clinical disease course after immunoablative therapy based on levels and avidity of ACPA-IgG indicates that refractory RA is not a single disease entity.     

Quantitative effects of vernalization on FLC and SOC1 expression

Prolonged exposure to cold results in early flowering in Arabidopsis winter annual ecotypes, with longer exposures resulting in a greater promotion of flowering than shorter exposures. The promotion of flowering is mediated through an epigenetic down-regulation of the floral repressor FLOWERING LOCUS C (FLC). We present results that provide an insight into the quantitative regulation of FLC by vernalization. Analysis of the effect of seed or plant cold treatment on FLC expression indicates that the time-dependent nature of vernalization on FLC expression is mediated through the extent of the initial repression of FLC and not by affecting the ability to maintain the repressed state. In the over-expression mutant flc-11, the time-dependent repression of FLC correlates with the proportional deacetylation of histone H3. Our results indicate that sequences within intron 1 and the activities of both VERNALIZATION1 (VRN1) and VERNALIZATION2 (VRN2) are required for efficient establishment of FLC repression; however, VRN1 and VRN2 are not required for maintenance of the repressed state during growth after the cold exposure. SUPPRESSOR OF OVER-EXPRESSION OF CO 1 (SOC1), a downstream target of FLC, is quantitatively induced by vernalization in a reciprocal manner to FLC. In addition, we show that SOC1 undergoes an acute induction by both short and long cold exposures.     

Transitional cell carcinoma of the ovary: A rare case and review of literature

Goblet cell carcinoid of the large intestine is a rare neoplasm, usually located in ascending colon and rectum. A 60-year-old male patient underwent surgery after the diagnosis of acute abdomen. Exploratory laparotomy revealed perforation with a diameter of 1 cm at the site of the previously performed gastroenterostomy and dilatation of the right colic flexure, secondary to a solid obstructive mass located in the mid-portion of transverse colon. Histopathological investigation of the biopsies, taken from the gastroenterostomy site and the tumor, revealed mixed carcinoid-adenocarcinoma with carcinoid component, predominantly composed of goblet cells. Three cycles of FOLFOX-4 protocol was administered. Following respiratory distress secondary to pulmonary metastasis, the patient's condition deteriorated and subsequently died in the fourth postoperative month. Our aim with this paper is to point out that more cases should be reported for more effective diagnosis, histopathological study, clinical investigation, treatment and prognosis of this specific neoplasm.     

Prospective cohort studies on risk factors for cardiovascular events in systemic lupus erythematosus: a major challenge

Cardiovascular disease (CVD) has been identified as a major contributor to morbidity and mortality in patients with systemic lupus erythematosus (SLE). The etiology of premature CVD in SLE is supposed to have many factors, including traditional coronary artery disease (CAD) risk factors, antiphospholipid antibodies, and metabolic and inflammatory factors. Despite the overwhelming interest in CVD in SLE research, prospective studies evaluating risk factors for hard endpoints (that is, cardiovascular events) are relatively scarce. The article by Gustafsson and colleagues suggests that prothrombotic factors play an important role in SLE-related CVD and that the influence of traditional CAD risk factors might be limited.     

An alternative oxidase monoclonal antibody recognises a highly conserved sequence among alternative oxidase subunits

The alternative oxidase is found in the inner mitochondrial membranes of plants and some fungi and protists. A monoclonal antibody raised against the alternative oxidase from the aroid lily Sauromatum guttatum has been used extensively to detect the enzyme in these organisms. Using an immunoblotting strategy, the antibody binding site has been localised to the sequence RADEAHHRDVNH within the soybean alternative oxidase 2 protein. Examination of sequence variants showed that A2 and residues C-terminal to H7 are required for recognition by the monoclonal antibody raised against the alternative oxidase. The recognition sequence is highly conserved among all alternative oxidase proteins and is absolutely conserved in 12 of 14 higher plant sequences, suggesting that this antibody will continue to be extremely useful in studying the expression and synthesis of the alternative oxidase.     

Analysis of the alternative oxidase promoters from soybean

Alternative oxidase (Aox) is a nuclear-encoded mitochondrial protein. In soybean (Glycine max), the three members of the gene family have been shown to be differentially expressed during normal plant development and in response to stresses. To examine the function of the Aox promoters, genomic fragments were obtained for all three soybean genes: Aox1, Aox2a, and Aox2b. The regions of these fragments immediately upstream of the coding regions were used to drive beta-glucuronidase (GUS) expression during transient transformation of soybean suspension culture cells and stable transformation of Arabidopsis. The expression patterns of the GUS reporter genes in soybean cells were in agreement with the presence or absence of the various endogenous Aox proteins, determined by immunoblotting. Deletion of different portions of the upstream regions identified sequences responsible for both positive and negative regulation of Aox gene expression in soybean cells. Reporter gene analysis in Arabidopsis plants showed differential tissue expression patterns driven by the three upstream regions, similar to those reported for the endogenous proteins in soybean. The expression profiles of all five members of the Arabidopsis Aox gene family were examined also, to compare with GUS expression driven by the soybean upstream fragments. Even though the promoter activity of the upstream fragments from soybean Aox2a and Aox2b displayed the same tissue specificity in Arabidopsis as they do in soybean, the most prominently expressed endogenous genes in all tissues of Arabidopsis were of the Aox1 type. Thus although regulation of Aox expression generally appears to involve the same signals in different species, different orthologs of Aox may respond variously to these signals. A comparison of upstream sequences between soybean Aox genes and similarly expressed Arabidopsis Aox genes identified common motifs.     

The HIV Env-mediated fusion reaction

The current general model of HIV viral entry involves the binding of the trimeric viral envelope glycoprotein gp120/gp41 to cell surface receptor CD4 and chemokine co-receptor CXCR4 or CCR5, which triggers conformational changes in the envelope proteins. Gp120 then dissociates from gp41, allowing for the fusion peptide to be inserted into the target membrane and the pre-hairpin configuration of the ectodomain to form. The C-terminal heptad repeat region and the leucine/isoleucine zipper region then form the thermostable six-helix coiled-coil, which drives the membrane merger and eventual fusion. This model needs updating, as there has been a wealth of data produced in the last few years concerning HIV entry, including target cell dependencies, fusion kinetic data, and conformational intermediates. A more complete model must include the involvement of membrane microdomains, actin polymerization, glycosphingolipids, and possibly CD4 and chemokine signaling in entry. In addition, kinetic experiments involving the addition of fusion inhibitors have revealed some of the rate-limiting steps in this process, adding a temporal component to the model. A review of these data that may require an updated version of the original model is presented here.     

IL-4 potentiates activated T cell apoptosis via an IL-2-dependent mechanism

Activation-induced cell death (AICD) of T cells is one of the major mechanisms of peripheral tolerance. The regulation of AICD by IL-4 is poorly understood. In this study, we report that AICD in IL-4-deficient T cells is significantly reduced compared with that in wild-type T cells. This impaired AICD correlates with the failure to induce degradation of cellular FLIP. IL-4-mediated enhancement of AICD and cellular FLIP degradation requires a Janus kinase/STAT-6 signaling pathway. Unexpectedly, these effects of IL-4 could be blocked by a neutralizing anti-IL-2 Ab, and addition of rIL-2 could completely restore the defective AICD in IL-4-deficient T cells. Furthermore, IL-4 regulates the T cell thresholds for IL-2 signaling during AICD. These data suggest that IL-4 promotes AICD via an IL-2-dependent mechanism.