To sialylate,or not to sialylate: that is the question

Most oropharyngeal pathogens express sialic acid units on their surfaces, mimicking the sialyl-rich mucin layer coating epithelial cells and the glycoconjugates present on virtually all host cell surfaces and serum proteins. Unlike the host's cells, which synthesize sialic acids endogenously, several microbial pathogens use truncated sialylation pathways. How microorganisms regulate sialic acid metabolism to ensure an adequate supply of free sugar for surface remodeling is a new area of research interest to basic scientists and those focused on the clinical outcome of the host-pathogen interaction.     

To be or not to be [fertile], that is the question

Background

According to our literature analysis, there are no data focused on spermatozoa emotional representations in childless men and data on the emotional repercussions of a diagnosis of infertility on men are still scarce. Thus, in this work, we investigated what the presence or absence of spermatozoa in the semen symbolize for men.

Material and methods

To answer this question, 441 childless heterosexual men participated in an anonymous, prospective, Internet-based survey.

Results

In response to the question “What would having a high or normal sperm count symbolize for you?” the most frequent answer was “ability to father a child”. Men living with a partner were significantly more likely than single men to answer “ability to father a child” (p?<?0.05) and less likely to answer “virility” and/or “ability to have an erection/ejaculation” (p?=?0.001). In response to the question “If you found out that you had a low sperm count or no spermatozoa at all, how would you feel?”, most of the men stated that they would be disappointed. Men living with a partner were more likely to state that they would feel ashamed (p?<?0.05) or guilty with regard to their partner (p?<?0.0001).

Conclusions

These preliminary results should help us to improve (i) the way that male infertility is announced (it is easier to find the right words if one understands the possible importance of having a high sperm count) and (ii) the psychological, marital and sexual counselling provided to men with a diagnosis of infertility.

     

To be helped or not helped,that is the question

Diphtheria toxin (DT)* is the paradigm of the powerful A-B toxins. These bacterial poisons bind to cells, are endocytosed, and inject their catalytic domain into the cytosol causing the irreversible modification of a key component of the the host cellular machinery. The mechanism by which the hydrophilic enzymatic fragment of DT crosses the endosomal membrane and is released into the cytosol remains controversial. In this issue, Ratts et al. (2003) demonstrate that delivery of the DT catalytic domain from the lumen of purified early endosomes to the external medium requires the addition of a cytosolic translocation factor complex composed in part of Hsp90 and thioredoxin reductase.     

To automate or not to automate: this is the question

New protocols and instrumentation significantly boost the outcome of structural biology, which has resulted in significant growth in the number of deposited Protein Data Bank structures. However, even an enormous increase of the productivity of a single step of the structure determination process may not significantly shorten the time between clone and deposition or publication. For example, in a medium size laboratory equipped with the LabDB and HKL-3000 systems, we show that automation of some (and integration of all) steps of the X-ray structure determination pathway is critical for laboratory productivity. Moreover, we show that the lag period after which the impact of a technology change is observed is longer than expected.     

To target or not to target APRIL in systemic lupus erythematosus: that is the question!

Among the cytokines that regulate B-cell homeostasis are the TNF-like ligands B-lymphocyte stimulator (BLyS; also B-cell activation factor) and a proliferation-inducing ligand (APRIL). BLyS and APRIL share two receptors; that is, B-cell maturation antigen and transmembrane activator and CAML interactor. Therapeutic approaches using biologics are limited for treatment of lupus patients. One previously approved drug is belimumab, which antagonizes the B-cell stimulator BLyS. Atacicept, another biologic inhibiting BLyS and APRIL, was terminated for serious adverse events - raising the question of whether APRIL should be neutralized in autoimmune diseases.Treamtrakanpon and coworkers analyzed B-lymphocyte stimulator (BLyS; also B-cell activation factor) and a proliferation-inducing ligand (APRIL) expression in patients with lupus nephritis and observed a correlation with renal disease activity and APRIL serum levels [1]. In addition, the authors describe that, upon treatment with immunosuppressors, nonresponding patients had higher APRIL serum levels. They thus concluded that APRIL could be a potential biomarker for predicting difficult-to-treat cases of lupus nephritis, and propose the use of APRIL antagonists such as atacicept for treatment of lupus nephritis patients with high APRIL serum levels.These conclusions might be premature, as Treamtrakanpon and coworkers have not found a correlation between the level of APRIL in kidney tissue and renal disease activity. Another hypothesis could be that APRIL has a protective effect in autoimmune diseases. Indeed, the crucial role of BLyS in B-cell maintenance became evident by the analysis of BLyS-deficient mice displaying lower numbers of mature B cells and of BLyS transgenic mice developing severe B-cell hyperplasia. Although APRIL can trigger different B-cell responses in vitro, including proliferation and survival of human and murine B cells, it is less critical than BLyS in B-cell maintenance as APRIL knockout and transgenic mice reveal no gross abnormalities in lymphoid homeostasis [2]. In fact, APRIL was found to modulate specific B-cell responses such as IgA isotype switching, increased IgM secretion and B1 cell activity.Meanwhile, BLyS is an established promoter of B-cell-triggered autoimmmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, whereas the role of APRIL in these pathologies is rather controversial. Neutralizing BLyS with the mAb belimumab displayed a modest, although statistically significant, therapeutic effect in systemic lupus erythematosus [3,4]. But blocking both BLyS and APRIL with atacicept (TACI-Fc) was associated with a pronounced reduction of immunoglobulins, and occurrence of serious infections led to a premature termination of a phase II/III trial in lupus nephritis [5]. The combination of mycofenolate mofetil with atacicept may have contributed to the decrease of immunoglobulins. However, at acicept combined with another drug such as methotrexate in patients with rheumatoid arthritis was also associated with a significant reduction of immunoglobulins (especially IgM). In this autoimmune disease, atacicept failed to demonstrate efficacy on American College of Rheumatology 20 criteria [6]. In contrast, administration of belimumab showed a modest but significant efficacy using the same evaluation criteria in rheumatoid arthritis [7].These findings suggest distinct roles for BLyS and APRIL in lupus and other B-cell-mediated autoimmune diseases. Elevated serum levels are found for both cytokines in lupus patients, and for BLyS there is a consensus in the literature that this reflects its disease-promoting activity. Elevated APRIL serum levels, however, have been - depending on the respective study - either positively or negatively correlated with disease features [8]. One possible explanation for this discrepancy could be differences in the patient cohorts analyzed. A recent study by Jacob and colleagues analyzed a murine lupus model in APRIL-deficient mice and observed elevated numbers of splenocytes, increased autoantibody production and a tendency towards increased IgG production [9]. Notably, ectopic APRIL expression does not result - in contrast to BLyS transgenic mice - in lupus-like symptoms. In fact, we found that APRIL does dampen collagen-induced arthritis, the most common mouse model for human arthritis [10].Experimental mouse models for autoimmune diseases obviously cannot entirely mimic human diseases. Nevertheless, in vivo data are accumulating that do not support a disease-supporting role for APRIL in B-cell-mediated autoimmunity. The study by Treamtrakanpon and colleagues is putting forward the need to better elucidate the role of APRIL in B-cell-driven diseases before concluding a therapeutic approach.     

To be, or not to be two sites: that is the question about LeuT substrate binding

Transport proteins of the neurotransmitter sodium symporter (NSS) family regulate the extracellular concentration of several neurotransmitters in the central nervous system. The only member of this family for which atomic-resolution structural data are available is the prokaryotic homologue LeuT. This protein has been used as a model system to study the molecular mechanism of transport of the NSS family. In this Journal Club, we discuss two strikingly different LeuT transport mechanisms: one involving a single high-affinity substrate binding site and one recently proposed alternative involving two high-affinity substrate binding sites that are allosterically coupled.     

To translocate or not: that is the problem

The botulinum toxins (BoNTs) enter the cytosol of host cells by translocation across the limiting membrane of acidic endosomes. In this issue, Sun et?al. (2011) show that BoNT binding to one of its cell surface receptors renders it susceptible to pH-dependent conformational changes required for translocation and cellular toxicity.     

PTB or not PTB -- that is the question

Phosphotyrosine binding (PTB) domains are structurally conserved modules found in proteins involved in numerous biological processes including signaling through cell-surface receptors and protein trafficking. While their original discovery is attributed to the recognition of phosphotyrosine in the context of NPXpY sequences -- a function distinct from that of the classical src homology 2 (SH2) domain -- recent studies show that these protein modules have much broader ligand binding specificities. These studies highlight the functional diversity of the PTB domain family as generalized protein interaction domains, and reinforce the concept that evolutionary changes of structural elements around the ligand binding site on a conserved structural core may endow these protein modules with the structural plasticity necessary for functional versatility.     

To kill or to arrest: that is the new question for Apaf-1

In this issue of Molecular Cell, Zermati et al. (2007) report that Apaf-1 is essential for the DNA damage-induced intra-S phase checkpoint response. This new role for Apaf-1 is unrelated to its proapoptotic function but is evolutionarily conserved in Ced-4.