Mannose-binding lectin deficiency is associated with early onset of polyarticular juvenile rheumatoid arthritis: a cohort study

Background  

Mannose-binding lectin (MBL) is an innate immune protein. The aim of our study was to determine whether genetically determined MBL deficiency is associated with susceptibility to juvenile rheumatoid arthritis (JRA) and whether MBL2 genotypes are associated with JRA severity.     

Influence of the calcium-induced gel phase on the behavior of small molecules in phosphatidylserine and phosphatidylserine-phosphatidylcholine multilamellar vesicles

The behavior of fluorescent and spin-label probes is examined in several fluid and gel phospholipid phases, with particular focus on the Ca2+-induced gel phase in phosphatidylserine (PS). These probes have behavior characteristic of the type of probe and of the type of lipid environment. Anthroyloxy- and doxyl-labeled PS [12-AS-PS and (7,6)PS, respectively] exhibit greatly restricted and/or slow probe motion in Ca(PS)2, even compared to thermotropic gel-phase lipid at the same temperature. In contrast, anthroyloxy- and doxyl-labeled phosphatidylcholine (PC), as well as fluorescent-labeled and spin-labeled fatty acid derivatives, show no apparent change in probe motion in Ca(PS)2 compared to fluid lamellar lipid. Doxyl-labeled phosphatidic acid, phosphatidylethanolamine, and phosphatidylglycerol show restricted motion in Ca(PS)2 relative to fluid-phase lipid, but the electron paramagnetic resonance (EPR) spectra could not be interpreted in terms of simple models for probe ordering. The fluorescent probes diphenylhexatriene (DPH) and trans-parinaric acid methyl ester (tPNA-Me) show motional behavior in Ca(PS)2 that is intermediate between that observed in fluid and in thermotropic gel-phase lipid. When Ca(PS)2 and fluid PS/PC phases coexist, probe molecules distribute between the two phases. Experiments using fluorescence quenching by spin-labeled PC in PS/PC in excess Ca2+ yield the distribution of several fluorophore probes between fluid liquid-crystal and Ca(PS)2 gel phases, expressed as a concentration ratio, RLC/G. The value of RLC/G = 100 in favor of the fluid phase is obtained for 12-AS-PC, 18 for 12-AS-Me, 12 for DPH, 3 for tPnA-Me, and 1 for 12-AS-PS.(ABSTRACT TRUNCATED AT 250 WORDS)     

A translocated bacterial protein protects vascular endothelial cells from apoptosis

The modulation of host cell apoptosis by bacterial pathogens is of critical importance for the outcome of the infection process. The capacity of Bartonella henselae and B. quintana to cause vascular tumor formation in immunocompromised patients is linked to the inhibition of vascular endothelial cell (EC) apoptosis. Here, we show that translocation of BepA, a type IV secretion (T4S) substrate, is necessary and sufficient to inhibit EC apoptosis. Ectopic expression in ECs allowed mapping of the anti-apoptotic activity of BepA to the Bep intracellular delivery domain, which, as part of the signal for T4S, is conserved in other T4S substrates. The anti-apoptotic activity appeared to be limited to BepA orthologs of B. henselae and B. quintana and correlated with (i) protein localization to the host cell plasma membrane, (ii) elevated levels of intracellular cyclic adenosine monophosphate (cAMP), and (iii) increased expression of cAMP-responsive genes. The pharmacological elevation of cAMP levels protected ECs from apoptosis, indicating that BepA mediates anti-apoptosis by heightening cAMP levels by a plasma membrane-associated mechanism. Finally, we demonstrate that BepA mediates protection of ECs against apoptosis triggered by cytotoxic T lymphocytes, suggesting a physiological context in which the anti-apoptotic activity of BepA contributes to tumor formation in the chronically infected vascular endothelium.     

Differential resistance across paternal genotypes of honey bee brood to the pathogenic bacterium Melissococcus plutonius

Melissococcus plutonius is a pathogenic bacterium affecting immature stages of the western honey bee (Apis mellifera) and leads to European foulbrood (EFB) disease. Despite EFB outbreaks increasing in frequency in several countries in recent decades, there is little knowledge on the epidemiology of M. plutonius or on the defence mechanisms of honey bees against this pathogen. Mating of honey bee queens with multiple males (polyandry) can be such a mechanism, as it has been shown to be beneficial to colony health and fitness. It is hypothesized that a high level of polyandry was selected for in response to pathogen pressure to maximize the probability that at least some patrilines among nestmates in a colony possess a high degree of resistance to specific pathogens, ultimately protecting colonies against infections. We show that M. plutonius infection provokes differential mortality among patrilines of immature honey bee workers. Such differences indicate a genetic origin of resistance against this pathogen—supporting the polyandry hypothesis—and open up avenues to improve control of EFB disease via selective breeding.     

Sexual signal evolution and patterns of assortative mating across an intraspecific contact zone

Contact zones provide important insights into the evolutionary processes that underlie lineage divergence and speciation. Here, we use a contact zone to ascertain speciation potential in the red-eyed treefrog (Agalychnis callidryas), a brightly coloured and polymorphic frog that exhibits unusually high levels of intraspecific variation. Populations of A. callidryas differ in a number of traits, several of which are known sexual signals that mediate premating reproductive isolation in allopatric populations. Along the Caribbean coast of Costa Rica, a ~100 km contact zone, situated between two phenotypically and genetically divergent parent populations, contains multiple colour pattern phenotypes and late-generation hybrids. This contact zone provides the opportunity to examine processes that are important in the earliest stages of lineage divergence. We performed analyses of colour pattern variation in five contact zone sites and six parental sites and found complex, continuous colour variation along the contact zone. We found discordance between the geographic distribution of colour pattern and previously described genomic population structure. We then used a parental site and contact zone site to measure assortative mating and directional selection from naturally-occurring amplectant mating pairs. We found assortative mating in a parental population, but no assortative mating in the contact zone. Furthermore, we uncovered evidence of directional preference towards the adjacent parental phenotype in the contact zone population, but no directional preference in the parent population. Combined, these data provide insights into potential dynamics at the contact zone borders and indicate that incipient speciation between parent populations will be slowed.     

Kidney Dysfunction in Adult Offspring Exposed In Utero to Type 1 Diabetes Is Associated with Alterations in Genome-Wide DNA Methylation

Background

Fetal exposure to hyperglycemia impacts negatively kidney development and function.

Objective

Our objective was to determine whether fetal exposure to moderate hyperglycemia is associated with epigenetic alterations in DNA methylation in peripheral blood cells and whether those alterations are related to impaired kidney function in adult offspring.

Design

Twenty nine adult, non-diabetic offspring of mothers with type 1 diabetes (T1D) (case group) were matched with 28 offspring of T1D fathers (control group) for the study of their leukocyte genome-wide DNA methylation profile (27,578 CpG sites, Human Methylation 27 BeadChip, Illumina Infinium). In a subset of 19 cases and 18 controls, we assessed renal vascular development by measuring Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) at baseline and during vasodilatation produced by amino acid infusion.

Results

Globally, DNA was under-methylated in cases vs. controls. Among the 87 CpG sites differently methylated, 74 sites were less methylated and 13 sites more methylated in cases vs. controls. None of these CpG sites were located on a gene known to be directly involved in kidney development and/or function. However, the gene encoding DNA methyltransferase 1 (DNMT1)—a key enzyme involved in gene expression during early development–was under-methylated in cases. The average methylation of the 74 under-methylated sites differently correlated with GFR in cases and controls.

Conclusion

Alterations in methylation profile imprinted by the hyperglycemic milieu of T1D mothers during fetal development may impact kidney function in adult offspring. The involved pathways seem to be a nonspecific imprinting process rather than specific to kidney development or function.     

Dissection of the influenza A virus endocytic routes reveals macropinocytosis as an alternative entry pathway

Influenza A virus (IAV) enters host cells upon binding of its hemagglutinin glycoprotein to sialylated host cell receptors. Whereas dynamin-dependent, clathrin-mediated endocytosis (CME) is generally considered as the IAV infection pathway, some observations suggest the occurrence of an as yet uncharacterized alternative entry route. By manipulating entry parameters we established experimental conditions that allow the separate analysis of dynamin-dependent and -independent entry of IAV. Whereas entry of IAV in phosphate-buffered saline could be completely inhibited by dynasore, a specific inhibitor of dynamin, a dynasore-insensitive entry pathway became functional in the presence of fetal calf serum. This finding was confirmed with the use of small interfering RNAs targeting dynamin-2. In the presence of serum, both IAV entry pathways were operational. Under these conditions entry could be fully blocked by combined treatment with dynasore and the amiloride derivative EIPA, the hallmark inhibitor of macropinocytosis, whereas either drug alone had no effect. The sensitivity of the dynamin-independent entry pathway to inhibitors or dominant-negative mutants affecting actomyosin dynamics as well as to a number of specific inhibitors of growth factor receptor tyrosine kinases and downstream effectors thereof all point to the involvement of macropinocytosis in IAV entry. Consistently, IAV particles and soluble FITC-dextran were shown to co-localize in cells in the same vesicles. Thus, in addition to the classical dynamin-dependent, clathrin-mediated endocytosis pathway, IAV enters host cells by a dynamin-independent route that has all the characteristics of macropinocytosis.