Inhibition of cGMP-dependent protein kinase II by its own splice isoform

cGMP- and cAMP-dependent protein kinases (cGK I, cGK II, and cAK) are important mediators of many signaling pathways that increase cyclic nucleotide concentrations and ultimately phosphorylation of substrates vital to cellular functions. Here we demonstrate a novel mRNA splice isoform of cGK II arising from alternative 5' splicing within exon 11. The novel splice variant encodes a protein (cGK II Delta(441-469)) lacking 29 amino acids of the cGK II Mg-ATP-binding/catalytic domain, including the conserved glycine-rich loop consensus motif Gly-x-Gly-x-x-Gly-x-Val which interacts with ATP in the protein kinase family of enzymes. cGK II Delta(441-469) has no intrinsic enzymatic activity itself, however, it antagonizes cGK II and cGK I, but not cAK. Thus, the activation and cellular functions of cGK II may be determined not only by intracellular cGMP levels but also by alternative splicing which may regulate the balance of expression of cGK II versus its own inhibitor, cGK II Delta(441-469).     

Analysis of HPC1, HPCX, and PCaP in Icelandic hereditary prostate cancer

Putative prostate cancer susceptibility loci have recently been identified by genetic linkage analysis on chromosomes 1q24-25 (HPC1). 1q44.243 (PCaP), and Xq27-28 (HPCX). In order to estimate the genetic linkage in Icelandic prostate cancer families, we genotyped 241 samples from 87 families with eleven markers in the HPC1 region, six markers at PCaP, and eight at HPCX. Concurrently, we assessed allelic imbalance at the HPC1 and PCaP loci in selected tumors from the patients. For each of the candidate regions, the combined parametric and non-parametric LOD scores were strongly negative. Evidence for linkage allowing for genetic heterogeneity was also insignificant for all the regions. The results were negative irrespective of whether calculations were performed for the whole material or for a selected set of early age at onset families. The prevalence of allelic imbalance was relatively low in both the HPC1 (0%-9%) and PCaP (5%-20%) regions and was not elevated in tumors from positively linked families. Our studies indicate that the putative cancer susceptibility genes at chromosomes 1q24-25, 1q44.2-43, and Xq27-28 are unlikely to contribute significantly to hereditary prostate cancer in Iceland and that selective loss of the HPC1 and PCaP loci is a relatively rare somatic event in prostate cancers.     

The phylogeny of the social Anelosimus spiders (Araneae: Theridiidae) inferred from six molecular loci and morphology

We use fragments of three nuclear genes (Histone 3, 18SrDNA, and 28SrDNA) and three mitochondrial genes (16SrDNA, ND1, and COI) totalling approximately 4.5kb, in addition to morphological data, to estimate the phylogenetic relationships among Anelosimus spiders, well known for their sociality. The analysis includes 67 individuals representing 23 of the 53 currently recognized Anelosimus species and all species groups previously recognized by morphological evidence. We analyse the data using Bayesian, maximum likelihood, and parsimony methods, considering the genes individually as well as combined (mitochondrial, nuclear, and both combined) in addition to a 'total evidence' analysis including morphology. Most of the data partitions are congruent in agreeing on several fundamental aspects of the phylogeny, and the combined molecular data yield a tree broadly similar to an existing morphological hypothesis. We argue that such congruence among data partitions is an important indicator of support that may go undetected by standard robustness estimators. Our results strongly support Anelosimus monophyly, and the monophyly of the recently revised American 'eximius lineage', although slightly altered by excluding A. pacificus. There was consistent support for the scattering of American Anelosimus species in three clades suggesting intercontinental dispersal. Several recently described species are reconstructed as monophyletic, supporting taxonomic decisions based on morphology and behaviour in this taxonomically difficult group. Corroborating previous results from morphology, the molecular data suggest that social species are scattered across the genus and thus that sociality has evolved multiple times, a significant finding for exploring the causes and consequences of social evolution in this group of organisms.     

The eunuch phenomenon: adaptive evolution of genital emasculation in sexually dimorphic spiders

Under natural and sexual selection traits often evolve that secure paternity or maternity through self‐sacrifice to predators, rivals, offspring, or partners. Emasculation—males removing their genitals—is an unusual example of such behaviours. Known only in insects and spiders, the phenomenon's adaptiveness is difficult to explain, yet its repeated origins and association with sexual size dimorphism (SSD) and sexual cannibalism suggest an adaptive significance. In spiders, emasculation of paired male sperm‐transferring organs — secondary genitals — (hereafter, palps), results in ‘eunuchs’. This behaviour has been hypothesized to be adaptive because (i) males plug female genitals with their severed palps (plugging hypothesis), (ii) males remove their palps to become better fighters in male–male contests (better‐fighter hypothesis), perhaps reaching higher agility due to reduced total body mass (gloves‐off hypothesis), and (iii) males achieve prolonged sperm transfer through severed genitals (remote‐copulation hypothesis). Prior research has provided evidence in support of these hypotheses in some orb‐weaving spiders but these explanations are far from general. Seeking broad macroevolutionary patterns of spider emasculation, we review the known occurrences, weigh the evidence in support of the hypotheses in each known case, and redefine more precisely the particular cases of emasculation depending on its timing in relation to maturation and mating: ‘pre‐maturation’, ‘mating’, and ‘post‐mating’. We use a genus‐level spider phylogeny to explore emasculation evolution and to investigate potential evolutionary linkage between emasculation, SSD, lesser genital damage (embolic breakage), and sexual cannibalism (females consuming their mates). We find a complex pattern of spider emasculation evolution, all cases confined to Araneoidea: emasculation evolved at least five and up to 11 times, was lost at least four times, and became further modified at least once. We also find emasculation, as well as lesser genital damage and sexual cannibalism, to be significantly associated with SSD. These behavioural and morphological traits thus likely co‐evolve in spiders. Emasculation can be seen as an extreme form of genital mutilation, or even a terminal investment strategy linked to the evolution of monogyny. However, as different emasculation cases in araneoid spiders are neither homologous nor biologically identical, and may or may not serve as paternity protection, the direct link to monogyny is not clear cut. Understanding better the phylogenetic patterns of emasculation and its constituent morphologies and behaviours, a clearer picture of the intricate interplay of natural and sexual selection may arise. With the here improved evolutionary resolution of spider eunuch behaviour, we can more specifically tie the evidence from adaptive hypotheses to independent cases, and propose promising avenues for further research of spider eunuchs, and of the evolution of monogyny.     

How Did the Spider Cross the River? Behavioral Adaptations for River-Bridging Webs in Caerostris darwini (Araneae: Araneidae)

Background

Interspecific coevolution is well described, but we know significantly less about how multiple traits coevolve within a species, particularly between behavioral traits and biomechanical properties of animals'' “extended phenotypes”. In orb weaving spiders, coevolution of spider behavior with ecological and physical traits of their webs is expected. Darwin''s bark spider (Caerostris darwini) bridges large water bodies, building the largest known orb webs utilizing the toughest known silk. Here, we examine C. darwini web building behaviors to establish how bridge lines are formed over water. We also test the prediction that this spider''s unique web ecology and architecture coevolved with new web building behaviors.

Methodology

We observed C. darwini in its natural habitat and filmed web building. We observed 90 web building events, and compared web building behaviors to other species of orb web spiders.

Conclusions

Caerostris darwini uses a unique set of behaviors, some unknown in other spiders, to construct its enormous webs. First, the spiders release unusually large amounts of bridging silk into the air, which is then carried downwind, across the water body, establishing bridge lines. Second, the spiders perform almost no web site exploration. Third, they construct the orb capture area below the initial bridge line. In contrast to all known orb-weavers, the web hub is therefore not part of the initial bridge line but is instead built de novo. Fourth, the orb contains two types of radial threads, with those in the upper half of the web doubled. These unique behaviors result in a giant, yet rather simplified web. Our results continue to build evidence for the coevolution of behavioral (web building), ecological (web microhabitat) and biomaterial (silk biomechanics) traits that combined allow C. darwini to occupy a unique niche among spiders.     

Bone mineral density and carotid atherosclerosis in systemic lupus erythematosus: a controlled cross-sectional study

IntroductionAs osteoporosis is reported to be associated with atherosclerosis in the general population we examined the relationship between bone mass and carotid measurements in patients with systemic lupus erythematosus (SLE) and controls, and possible links between them in SLE.MethodsIn a cross-sectional study, 111 SLE-patient were compared with 111 age- and sex-matched controls, mean age 48.7(12.9) years, 89% were women, of which 51% postmenopausal. Carotid intima media thickness (cIMT), carotid plaque occurrence and echogenicity were determined by B-mode ultrasound and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA).ResultsBMD and cIMT were inversely associated both in patients and controls. Patients, but not controls, with carotid plaque had higher cIMT at low BMD than at normal BMD, p = 0.010. Logistic regression indicated more than doubled odds ratio (OR) of carotid plaque in patients, particularly in post-menopausal women, than in controls in relation to all BMD measurements. For low BMD at hip, significant increased OR for echolucent plaque was shown for patients compared with controls.In patients, significant impact of age, body mass index, smoking, systolic blood pressure, blood lipids, diabetes mellitus, impaired renal function, low levels of complement C3 and C4, history of nephritis, SLE-damage index and ever use of antimalarial was found for association between BMD and higher cIMT and carotid plaque. In multivariate regression, low C4 was independent contributor to association between total BMD and upper cIMT tertile, accounted for OR (95% confidence interval) of 3.2 (1.03-10.01), and also for association with bilateral carotid plaque, OR of 4.8 (1.03-22.66). The contribution of low C4 for the association between BMD and carotid atherosclerosis was enhanced within the second and third tertiles of total BMD.ConclusionThis study is the first to demonstrate inverse association between BMD and carotid measurements in both SLE-patients and controls. Our results suggest that SLE-patients may suffer higher burden of (sub)clinical atherosclerotic disease, especially presence of both echolucent and echogenic plaque, than controls with the same bone mineral status. Low complement C4 seems to play an important role in earlier development of carotid atherosclerosis already within (sub)normal ranges of total BMD in patients.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0595-4) contains supplementary material, which is available to authorized users.     

Serinc, an activity-regulated protein family, incorporates serine into membrane lipid synthesis

Cell membranes contain various transporter proteins, some of which are responsible for transferring amino acids across membrane. In this study, we report another class of carrier proteins, termed Serinc1-5, that incorporates a polar amino acid serine into membranes and facilitates the synthesis of two serine-derived lipids, phosphatidylserine and sphingolipids. Serinc is a unique protein family that shows no amino acid homology to other proteins but is highly conserved among eukaryotes. The members contain 11 transmembrane domains, and rat Serinc1 protein co-localizes with lipid biosynthetic enzymes in endoplasmic reticulum membranes. A Serinc protein forms an intracellular complex with key enzymes involved in serine and sphingolipid biosyntheses, and both functions, serine synthesis and membrane incorporation, are linked to each other. In the rat brain, expression of Serinc1 and Serinc2 mRNA was rapidly up-regulated by kainate-induced seizures in neuronal cell layers of the hippocampus. In contrast, myelin throughout the brain is enriched with Serinc5, which was down-regulated in the hippocampus by seizures. These results indicate a novel mechanism linking neural activity and lipid biosynthesis.     

Cellular signaling mediated by calphoglin-induced activation of IPP and PGM

Universal protein networks conserved from bacteria to animals dictate the core functions of cells. Inorganic pyrophosphatase (IPP) is an essential enzyme that plays a pivotal role in a broad spectrum of cellular biosynthetic reactions such as amino acid, nucleotide, polysaccharide, and fatty acid biosynthesis. However, the in vivo cellular regulation mechanisms of IPP and another key metabolic enzyme, phosphoglucomutase (PGM), remain unknown. This study aimed to examine the universal protein regulatory network by utilizing genome sequences, yeast proteomic data, and phosphoryl-transfer experiments. Here we report a novel human protein, henceforth referred to as calphoglin, which interacts with IPP and activates it. Calphoglin enhances PGM activity through the activated IPP and more directly on its own. Protein structure and assembly, catalytic function, and ubiquitous cellular localization of the calphoglin (-IPP-PGM) complex were conserved among Escherichia coli, yeast, and mammals. In the rat brain, calphoglin mRNA was enriched in the hippocampus and the cerebellum. Further, the linkage of the calphoglin complex to calcium signaling was demonstrated by its interactive co-localization within the calmodulin/calcineurin signaling complex, by Ca(2+)-binding and Ca(2+)-controlled activity of calphoglin-IPP, and by calphoglin-induced enhancement of microsomal Ca(2+) uptake. Collectively, these results suggest that the calphoglin complex is a common mechanism utilized in mediating bacterial cell metabolism and Ca(2+)/calmodulin/calcineurin-dependent mammalian cell activation. This is the first report of an activator of IPP and PGM, a function novel to proteins.     

Gluten-free vegan diet induces decreased LDL and oxidized LDL levels and raised atheroprotective natural antibodies against phosphorylcholine in patients with rheumatoid arthritis: a randomized study

Introduction

The purpose of this study was to investigate the effects of vegan diet in patients with rheumatoid arthritis (RA) on blood lipids oxidized low-density lipoprotein (oxLDL) and natural atheroprotective antibodies against phosphorylcholine (anti-PCs).

Methods

Sixty-six patients with active RA were randomly assigned to either a vegan diet free of gluten (38 patients) or a well-balanced non-vegan diet (28 patients) for 1 year. Thirty patients in the vegan group completed more than 3 months on the diet regimen. Blood lipids were analyzed by routine methods, and oxLDL and anti-PCs were analyzed by enzyme-linked immunosorbent assay. Data and serum samples were obtained at baseline and after 3 and 12 months.

Results

Mean ages were 50.0 years for the vegan group and 50.8 years for controls. Gluten-free vegan diet induced lower body mass index (BMI) and low-density lipoprotein (LDL) and higher anti-PC IgM than control diet (p < 0.005). In the vegan group, BMI, LDL, and cholesterol decreased after both 3 and 12 months (p < 0.01) and oxLDL after 3 months (p = 0.021) and trendwise after 12 months (p = 0.090). Triglycerides and high-density lipoprotein did not change. IgA anti-PC levels increased after 3 months (p = 0.027) and IgM anti-PC levels increased trendwise after 12 months (p = 0.057). There was no difference in IgG anti-PC levels. In the control diet group, IgM anti-PC levels decreased both after 3 and 12 months (p < 0.01). When separating vegan patients into clinical responders and non-responders at 12 months, the effects on oxLDL and anti-PC IgA were seen only in responders (p < 0.05).

Conclusion

A gluten-free vegan diet in RA induces changes that are potentially atheroprotective and anti-inflammatory, including decreased LDL and oxLDL levels and raised anti-PC IgM and IgA levels.