ARNTL,CLOCK and PER3 polymorphisms – links with chronotype and affective dimensions

Recently, seven single nucleotide polymorphisms (SNPs) of ARNTL, TIM and PER3 genes were found associated with affective temperaments in bipolar disorder patients. This study aimed to test whether a) the same associations appear in a non-clinical sample; b) the SNPs are related to other affective dimensions; c) the SNPs underpin the associations between chronotype and affective temperaments/dimensions. Three hundred thirty-eight university students completed the Temperament Scale of Memphis, Pisa, Paris and San Diego Auto-questionnaire, the Centre for Epidemiological Studies Depression Scale, the Perceived Stress Scale, the General Health Questionnaire, the Seasonal Pattern Assessment Questionnaire and the Composite Scale of Morningness. Seven SNPs of the ARNTL, TIM and PER3 genes were genotyped. According to nominal significance, ARNTL rs7107287 was associated with a cyclothymic temperament, depressive and stress symptoms, general mental health and perceived negative impact of seasonality, while TIM rs10876890 was associated with a hyperthymic temperament, and the TIM rs2291738 was associated with chronotype. Different SNPs were related to chronotype and affective temperaments/dimensions, and therefore, they seem to not underpin relationships between chronotype and affective dysfunction, that is, in the present study, eveningness was related to dysthymic, cyclothymic and irritable temperaments, more symptoms of depression, stress, worse mental health and a negative impact of seasonality, while morningness was related to hyperthymic temperament. The SNPs associations need further replication given that they did not achieve Bonferroni criteria of significance accounting for the number of polymorphisms considered and tests conducted.     

Biallelic mutations in <Emphasis Type="Italic">CYP24A1</Emphasis> or <Emphasis Type="Italic">SLC34A1</Emphasis> as a cause of infantile idiopathic hypercalcemia (IIH) with vitamin D hypersensitivity: molecular study of 11 historical IIH cases

Idiopathic infantile hypercalcemia (IIH) is a mineral metabolism disorder characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. The periodical increase in incidence of IIH, which occurred in the twentieth century in the United Kingdom, Poland, and West Germany, turned out to be a side effect of rickets over-prophylaxis. It was recently discovered that the condition is linked to two genes, CYP24A1 and SLC34A1. The aim of the study was to search for pathogenic variants of the genes in adult persons who were shortlisted in infancy as IIH caused by “hypersensitivity to vit. D”. All persons were found to carry mutations in CYP24A1 or SLC34A1, nine and two persons respectively. The changes were biallelic, with one exception. Incidence of IIH in Polish population estimated on the basis of allele frequency of recurrent p.R396W CYP24A1 variant, is 1:32,465 births. It indicates that at least a thousand homozygotes and compound heterozygotes with risk of IIH live in the country. Differences in mechanism of developing hypercalcemia indicate that its prevention may vary in both IIH defects. Theoretically, vit. D restriction is a first indication for CYP24A1 defect (which disturbs 1,25(OH)₂D degradation) and phosphate supplementation for SLC34A1 defect (which impairs renal phosphate transport). In conclusion, we suggest that molecular testing for CYP24A1 and SLC34A1 mutations should be performed in each case of idiopathic hypercalcemia/hypercalciuria, both in children and adults, to determine the proper way for acute treatment and complications prevention.     

Resource use by the dryad butterfly is scale-dependent

The factors shaping the ways in which animals use resources are a key element of conservation biology, but ecological studies on resource use typically neglect to consider how the study’s spatial scale may have affected the outcomes. We used the dryad butterfly, inhabiting xerothermic grassland and wet meadow, to test for differences in its resource use at two scales–habitat patch and landscape. Based on records of plant species composition from random points within four habitat patches and from points in 53 patches along surveyed transects, we compared the microhabitat preferences of the butterfly on the patch scale, and species occurrence and abundance patterns on the landscape scale. We distinguished four main groups of factors related to vegetation structure which affected the butterfly’s resource use—factors having similar effects on both spatial scales, factors operating primarily on one of the scales considered, factors relevant only on a single spatial scale, and factors operating on both scales but with effects differing between the two habitat types. We suggest that invertebrates may respond on two spatial levels or on only one, and conclude that larger-scale studies can meet the challenges of a sophisticated metapopulation approach and can give insight into the habitat characteristics affecting the persistence of species in landscapes. We stress the value of large-scale studies on species’ habitat preferences when planning conservation strategies, while pointing out that small-scale studies provide useful information about species ecology and behavior, especially if conducted in multiple habitats.     

Environmental Assessment of Waste-Solvent Treatment Options

A comparison of various waste‐solvent treatment technologies, such as distillation (rectification) and incineration in hazardous‐waste‐solvent incinerators and cement kilns, is presented for 45 solvents with respect to the environmental life‐cycle impact. The environmental impact was calculated with the ecosolvent tool that was previously described in Part I of this work. A comprehensive sensitivity analysis was performed, and uncertainties were quantified by stochastic modeling in which various scenarios were considered. The results show that no single treatment technology is generally environmentally superior to any other but that, depending on the solvent mixture and the process conditions, each option may be optimal in certain cases. Nevertheless, various rules of thumb could be derived, and a results table is presented for the 45 solvents showing under which process conditions and amount of solvent recovery distillation is environmentally superior to incineration. On the basis of these results and the ecosolvent tool, an easily usable framework was developed that helps decision makers in chemical industries reduce environmental burdens throughout the solvent life cycle. With clear recommendations on the environmentally optimized waste‐solvent treatment technology, the use of this framework contributes to more environmentally sustainable solvent management and thus represents a practical application of industrial ecology.     

Structural flexibility in proteins: impact of the crystal environment

MOTIVATION: In the study of the structural flexibility of proteins, crystallographic Debye-Waller factors are the most important experimental information used in the calibration and validation of computational models, such as the very successful elastic network models (ENMs). However, these models are applied to single protein molecules, whereas the experiments are performed on crystals. Moreover, the energy scale in standard ENMs is undefined and must be obtained by fitting to the same data that the ENM is trying to predict, reducing the predictive power of the model. RESULTS: We develop an elastic network model for the whole protein crystal in order to study the influence of crystal packing and lattice vibrations on the thermal fluctuations of the atom positions. We use experimental values for the compressibility of the crystal to establish the energy scale of our model. We predict the elastic constants of the crystal and compare with experimental data. Our main findings are (1) crystal packing modifies the atomic fluctuations considerably and (2) thermal fluctuations are not the dominant contribution to crystallographic Debye-Waller factors. AVAILABILITY: The programs developed for this work are available as supplementary material at Bioinformatics Online.     

Trans-epithelial immune cell transfer during suckling modulates delayed-type hypersensitivity in recipients as a function of gender

Introduction

Breast feeding has long term effects on the developing immune system which outlive passive immunization of the neonate. We have investigated the transfer of milk immune cells and examined the result of transfer once the recipients were adult.

Methods

Non-transgenic mouse pups were foster-nursed by green fluorescent protein (GFP) transgenic dams for 3 weeks and the fate of GFP+ cells was followed by FACS analysis, immunohistochemistry and RT-PCR for GFP and appropriate immune cell markers. Pups suckled by non-transgenic dams served as controls.

Results

Despite a preponderance of B cells and macrophages in the stomach contents of the pups, most cells undergoing trans-epithelial migration derived from the 3–4% of milk cells positive for T lymphocyte markers. These cells homed to the spleen and thymus, with maximal accumulation at 3–4 weeks. By sensitizing dams with an antigen which elicits a T cell-mediated delayed-type-hypersensitivity (DTH) response, we determined that nursing by a sensitized dam (compared to a non-sensitized dam) amplified a subsequent DTH response in females and yet suppressed one in males.

Discussion

These results suggest that clinical evaluation weighing the pros and cons of nursing male versus female children by mothers with genetically-linked hypersensitivity diseases, such as celiac disease and eczema, or those in regions of the world with endemic DTH-eliciting diseases, such as tuberculosis, may be warranted.     

Signal-induced repression: the exception or the rule in developmental signaling?

Cell-cell communication plays a key role in organ formation and patterning in multicellular animals and is carried out by a few evolutionarily conserved signaling pathways. The modes of action of these pathways share a number of general properties, or habits, that allow them to strongly activate target genes in a ligand-dependent manner in the proper cellular contexts. Recent studies have revealed that some developmental signaling pathways can also strongly repress genes in a ligand-dependent manner. These new findings raise the interesting possibility that this repressive mode of action is shared by many or most developmental signaling pathways.     

A novel splicing variant of proprotein convertase subtilisin/kexin type 9

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the most recently identified member of the proprotein convertase family. Genetic and cell biology studies have suggested a critical role of PCSK9 in regulating low-density lipoprotein receptor (LDLR) protein levels and thus modulating plasma LDL cholesterol. Recent data on the molecular basis for PCSK9 action support the model in which PCSK9 is self-cleaved, secreted, and tightly bound to the EGF-A repeat of LDLR extracellular domain. PCSK9 binding to LDLR is essential for the ensuing receptor-mediated endocytosis and is speculated to lock LDLR in a specific conformation that favors degradation in lysosomal compartment instead of recycling back to plasma membrane. We report here a novel human PCSK9 splicing variant, which we named PCSK9sv. PCSK9sv had an in-frame deletion of the eighth exon of 58 amino acids and was expressed in multiple tissues, including liver, small intestine, prostate, uterus, brain, and adipose tissue. Unlike wild-type PCSK9, which is secreted, PCSK9sv expressed in human embryonic kidney HEK293 cells failed to process the prosegment intracellularly and thus was not secreted into the medium. Examination of potential functions revealed that PCSK9sv did not change the LDLR protein levels. Two mutations that have been reported in humans with the associated changes in plasma LDL cholesterol were within exon 8, and thus the expression and function of the two mutants were studied. Both N425S and A443T mutants were processed normally, secreted, and reduced LDLR levels. However, the physiological function of this novel splicing variant of PCSK9 has yet to be determined.