Mapping a new spontaneous preterm birth susceptibility gene, IGF1R, using linkage, haplotype sharing, and association analysis

Preterm birth is the major cause of neonatal death and serious morbidity. Most preterm births are due to spontaneous onset of labor without a known cause or effective prevention. Both maternal and fetal genomes influence the predisposition to spontaneous preterm birth (SPTB), but the susceptibility loci remain to be defined. We utilized a combination of unique population structures, family-based linkage analysis, and subsequent case-control association to identify a susceptibility haplotype for SPTB. Clinically well-characterized SPTB families from northern Finland, a subisolate founded by a relatively small founder population that has subsequently experienced a number of bottlenecks, were selected for the initial discovery sample. Genome-wide linkage analysis using a high-density single-nucleotide polymorphism (SNP) array in seven large northern Finnish non-consanginous families identified a locus on 15q26.3 (HLOD 4.68). This region contains the IGF1R gene, which encodes the type 1 insulin-like growth factor receptor IGF-1R. Haplotype segregation analysis revealed that a 55 kb 12-SNP core segment within the IGF1R gene was shared identical-by-state (IBS) in five families. A follow-up case-control study in an independent sample representing the more general Finnish population showed an association of a 6-SNP IGF1R haplotype with SPTB in the fetuses, providing further evidence for IGF1R as a SPTB predisposition gene (frequency in cases versus controls 0.11 versus 0.05, P = 0.001, odds ratio 2.3). This study demonstrates the identification of a predisposing, low-frequency haplotype in a multifactorial trait using a well-characterized population and a combination of family and case-control designs. Our findings support the identification of the novel susceptibility gene IGF1R for predisposition by the fetal genome to being born preterm.     

Tolerance to Diazepam-Induced Motor Impairment: A Study with GABAA Receptor α6 Subunit Knockout Mice

Development of tolerance to motor-impairing effects of repeated administration of moderate diazepam doses (5.0–7.5 mg/kg; three times daily PO 3 weeks) was compared between mice deficient in the cerebellar granule cell–restricted GABA_A receptor 6 subunit and their wild-type controls. The 6–/– mice were more impaired by the initial challenge doses of diazepam (5 or 10 mg/kg) than their controls, but acquired partial tolerance by the second tests with the same doses 4–7 days later. Chronic treatment produced complete tolerance in both mouse lines. Ligand autoradiography revealed a significant reduction in baseline benzodiazepine and chloride channel site-bindings in various regions of the 6–/– brains, but the chronic diazepam treatment did not consistently alter baseline or benzodiazepine site agonist and inverse agonist-modulated binding in the 6–/– and wildtype mice. The results indicate that tolerance to motor-impairing actions of diazepam is independent of the diazepam-insensitive 6 subunit-containing receptors, which rules out the possibility that tolerance emerges as an increase in structurally benzodiazepine-insensitive receptor population.     

Network Adaptation Improves Temporal Representation of Naturalistic Stimuli in Drosophila Eye: II Mechanisms

Retinal networks must adapt constantly to best present the ever changing visual world to the brain. Here we test the hypothesis that adaptation is a result of different mechanisms at several synaptic connections within the network. In a companion paper (Part I), we showed that adaptation in the photoreceptors (R1–R6) and large monopolar cells (LMC) of the Drosophila eye improves sensitivity to under-represented signals in seconds by enhancing both the amplitude and frequency distribution of LMCs'' voltage responses to repeated naturalistic contrast series. In this paper, we show that such adaptation needs both the light-mediated conductance and feedback-mediated synaptic conductance. A faulty feedforward pathway in histamine receptor mutant flies speeds up the LMC output, mimicking extreme light adaptation. A faulty feedback pathway from L2 LMCs to photoreceptors slows down the LMC output, mimicking dark adaptation. These results underline the importance of network adaptation for efficient coding, and as a mechanism for selectively regulating the size and speed of signals in neurons. We suggest that concert action of many different mechanisms and neural connections are responsible for adaptation to visual stimuli. Further, our results demonstrate the need for detailed circuit reconstructions like that of the Drosophila lamina, to understand how networks process information.     

Network Adaptation Improves Temporal Representation of Naturalistic Stimuli in Drosophila Eye: I Dynamics

Because of the limited processing capacity of eyes, retinal networks must adapt constantly to best present the ever changing visual world to the brain. However, we still know little about how adaptation in retinal networks shapes neural encoding of changing information. To study this question, we recorded voltage responses from photoreceptors (R1–R6) and their output neurons (LMCs) in the Drosophila eye to repeated patterns of contrast values, collected from natural scenes. By analyzing the continuous photoreceptor-to-LMC transformations of these graded-potential neurons, we show that the efficiency of coding is dynamically improved by adaptation. In particular, adaptation enhances both the frequency and amplitude distribution of LMC output by improving sensitivity to under-represented signals within seconds. Moreover, the signal-to-noise ratio of LMC output increases in the same time scale. We suggest that these coding properties can be used to study network adaptation using the genetic tools in Drosophila, as shown in a companion paper (Part II).     

In vivo activation of autoreactive cytotoxic T lymphocytes after bone marrow transplantation: evidence for the prethymic specificity of T cells?

The light density fraction (A + B, i.e., remaining above the 26% concentration in the discontinuous BSA gradient) of BCF1 (H-2b X H-2k) mouse bone marrow contains cells that after injection into irradiated syngeneic recipients give rise to autoreactive Lyt-2+, Thy-1+ CTL. After injection of unfractionated bone marrow cells, the levels of these CTL were low or undetectable, suggesting that either the precursors were highly enriched in the A + B fraction or that bone marrow cells with higher density have a suppressive function. The specificity of the killing was not directed toward all the available class I MHC antigens: only targets carrying H-2Kb-coded determinants were killed. There was no overlapping between the autoreactive and alloreactive precursors: cells from the A + B fraction could not respond to an alloantigen in vitro, not even in the presence of an interleukin 2-containing supernatant, and the autoreactive CTL activated in vivo could not kill allogeneic targets. The induction of the autoreactive CTL did not require the presence of the appropriate MHC antigen in the maturation environment, thus differing from the activation of mature T cells. The observed CTL specificity, together with the previous findings showing that prethymic T cells are locating in the same BSA fraction as the precursors for these autoreactive cells, support the idea that the prethymic T cell repertoire is, at least partially, directed to recognize self-MHC antigens.     

Separation and characterization of two chemically distinct lipopolysaccharides in two Pectinatus species.

Lipopolysaccharides (LPS) from the type strains of the anaerobic beer spoilage bacteria Pectinatus cerevisiiphilus and P. frisingensis were extracted with the 5:5:8 volume ratio modification of the phenolchloroform-petroleum ether method (H. Brade and C. Galanos, Eur. J. Biochem. 122:233-237, 1982). Sequential precipitations of LPS with water and acetone from the phenol phase yielded LPS which differed in that water-precipitable material (LPS-H2O; 0.1 to 0.4% of the dry weight of the cells) was rough-type LPS, whereas acetone-precipitable material (LPS-Ac; 4.6 to 5.8% of the dry weight) contained both rough-type LPS and high-molecular-weight material resembling smooth LPS. The LPS were chemically characterized, and they contained D-glucosamine, 4-amino-4-deoxy-L-arabinose, 3-deoxy-D-manno-2-octulosonic acid, D-fucose, D-galactose, D-glucose, D-mannose, and phosphate. D-Fucose was present mostly in LPS-Ac, suggesting that it is a constituent of the O antigen. The major fatty acids were ester- and amide-linked (R)-3-hydroxytridecanoic and ester-linked undecanoic acids, with minor amounts of ester-linked tridecanoic and (R)-3-hydroxyundecanoic acids. The chemical compositions of LPS-H2O and LPS-Ac suggested that they differ not only in their smooth or rough nature but also in the structure of their core regions. This may explain their different precipitabilities from the extraction mixture. The extraction method was also shown to be applicable to the isolation of smooth-type LPS from Salmonella enterica serovar Typhimurium. Extraction of two Typhimurium strains carrying chemically different O antigens resulted in high yields (8% of the dry weight) of LPS. Strain SH2183, which contains the relatively hydrophobic O-4,5,12 antigen yielded almost exclusively LPS-Ac, whereas the LPS of strain SH5770, which has a hydrophilic O-6,7 antigen, was exclusively LPS-H2O. No fractionation to smooth and rough LPS occurred with the Typhimurium strains.     

Permanent night workers´ sleep and psychosocial factors in hospital work. A comparison to day and shift work

ABSTRACT

We aimed to study whether permanent night workers sleep and psychosocial factors differ from day workers and shift workers. The participants (n = 9 312, 92% females, average age 45 years, most commonly nurses and departmental secretaries) were day workers (DW, n = 2 672), shift workers (SW, n = 6 486) and permanent night workers (PNW, n = 154). The Finnish Public Sector survey responses from six hospital districts from 2012 were combined to payroll data from 91 days preceding the survey. The data were analyzed using Pearson χ²-test, one-way ANOVA and multinomial logistic regression analysis. The PNWs reported slightly longer average sleep length than the SWs or the DWs (7:27 vs. 7:13 and 7:10 h, p < 0.001). The PNWs reported least often difficulties in maintaining sleep (p < 0.001) compared to the SWs and the DWs. The PNWs reported most often difficulties to fall asleep and fatigue during free-time (p-values <0.001). The DWs and PNWs experienced less often work-life conflict than the SWs (25 and 26 vs. 38%, p < 0.001). The PNWs were more often satisfied with autonomy at work and appreciation and fair treatment by colleagues than the DWs or the SWs (p < 0.001). The SWs and PNWs reported remarkably higher occurrence of verbal (p < 0.001, OR 3.71, 95% CI 3.23–4.27 and OR 7.67, 95% CI 5.35–10.99, respectively) and physical workplace violence (p < 0.001, OR 9.24, 95% CI 7.17–11.90 and OR 28.34, 95% CI 16.64–43.06, respectively) compared to DWs. Conclusively, PNWs reported contradictory differences in sleep quality compared to DWs and SWs. PNWs are more often satisfied with their colleagues and autonomy at work than DWs or SWs but face workplace violence remarkably more often.