Evidence of association with type 1 diabetes in the SLC11A1 gene region

BackgroundLinkage and congenic strain analyses using the nonobese diabetic (NOD) mouse as a model for human type 1 autoimmune diabetes (T1D) have identified several NOD mouse Idd (insulin dependent diabetes) loci, including Slc11a1 (formerly known as Nramp1). Genetic variants in the orthologous region encompassing SLC11A1 in human chromosome 2q35 have been reported to be associated with various immune-related diseases including T1D. Here, we have conducted association analysis of this candidate gene region, and then investigated potential correlations between the most T1D-associated variant and RNA expression of the SLC11A1 gene and its splice isoform.MethodsNine SNPs (rs2276631, rs2279015, rs1809231, rs1059823, rs17235409 (D543N), rs17235416 (3'UTR), rs3731865 (INT4), rs7573065 (-237 C → T) and rs4674297) were genotyped using TaqMan genotyping assays and the polymorphic promoter microsatellite (GT)n was genotyped using PCR and fragment length analysis. A maximum of 8,863 T1D British cases and 10,841 British controls, all of white European descent, were used to test association using logistic regression. A maximum of 5,696 T1D families were also tested for association using the transmission/disequilibrium test (TDT). We considered P ≤ 0.005 as evidence of association given that we tested nine variants in total. Upon identification of the most T1D-associated variant, we investigated the correlation between its genotype and SLC11A1 expression overall or with splice isoform ratio using 42 PAXgene whole blood samples from healthy donors by quantitative PCR (qPCR).ResultsUsing the case-control collection, rs3731865 (INT4) was identified to be the variant most associated with T1D (P = 1.55 × 10-6). There was also some evidence of association at rs4674297 (P = 1.57 × 10-4). No evidence of disease association was obtained at any of the loci using the family collections (PTDT ≥ 0.13). We also did not observe a correlation between rs3731865 genotypes and SLC11A1 expression overall or with splice isoform expression.ConclusionWe conclude that rs3731685 (INT4) in the SLC11A1 gene may be associated with T1D susceptibility in the European ancestry population studied. We did not observe a difference in SLC11A1 expression at the RNA level based on the genotypes of rs3731865 in whole blood samples. However, a potential correlation cannot be ruled out in purified cell subsets especially monocytes or macrophages

Altered hippocampal function in major depression despite intact structure and resting perfusion

Background: Hippocampal volume reductions in major depression have been frequently reported. However, evidence for functional abnormalities in the same region in depression has been less clear. We investigated hippocampal function in depression using functional magnetic resonance imaging (fMRI) and neuropsychological tasks tapping spatial memory function, with complementing measures of hippocampal volume and resting blood flow to aid interpretation. Method: A total of 20 patients with major depressive disorder (MDD) and a matched group of 20 healthy individuals participated. Participants underwent multimodal magnetic resonance imaging (MRI): fMRI during a spatial memory task, and structural MRI and resting blood flow measurements of the hippocampal region using arterial spin labelling. An offline battery of neuropsychological tests, including several measures of spatial memory, was also completed. Results: The fMRI analysis showed significant group differences in bilateral anterior regions of the hippocampus. While control participants showed task-dependent differences in blood oxygen level-dependent (BOLD) signal, depressed patients did not. No group differences were detected with regard to hippocampal volume or resting blood flow. Patients showed reduced performance in several offline neuropsychological measures. All group differences were independent of differences in hippocampal volume and hippocampal blood flow. Conclusions: Functional abnormalities of the hippocampus can be observed in patients with MDD even when the volume and resting perfusion in the same region appear normal. This suggests that changes in hippocampal function can be observed independently of structural abnormalities of the hippocampus in depression

Logarithmic temperature profiles in turbulent Rayleigh-B\'enard convection

We report results for the temperature profiles of turbulent Rayleigh-B\'enard convection (RBC) in the interior of a cylindrical sample of aspect ratio $\Gamma \equiv D/L = 0.50$ ($D$ and $L$ are the diameter and height respectively). Results from experiment over the Rayleigh number range 4\times 10^{12} \alt Ra \alt 10^{15} for a Prandtl number \Pra \simeq 0.8 and from direct numerical simulation (DNS) at $Ra = 2 \times 10^{12}$ for \Pra = 0.7 are presented. We find that the temperature varies as $A*ln(z/L) + B$ where $z$ is the distance from the bottom or top plate. This is the case in the classical as well as in the ultimate state of RBC. From DNS we find that $A$ in the classical state decreases in the radial direction as the distance from the side wall increases and becomes small near the sample center

Cdk1 inactivation terminates mitotic checkpoint surveillance and stabilizes kinetochore attachments in anaphase

Two mechanisms safeguard the bipolar attachment of chromosomes in mitosis. A correction mechanism destabilizes erroneous attachments that do not generate tension across sister kinetochores [1]. In response to unattached kinetochores, the mitotic checkpoint delays anaphase onset by inhibiting the anaphase-promoting complex/cyclosome (APC/CCdc20) [2]. Upon satisfaction of both pathways, the APC/CCdc20 elicits the degradation of securin and cyclin B [3]. This liberates separase triggering sister chromatid disjunction and inactivates cyclin-dependent kinase 1 (Cdk1) causing mitotic exit. How eukaryotic cells avoid the engagement of attachment monitoring mechanisms when sister chromatids split and tension is lost at anaphase is poorly understood [4]. Here we show that Cdk1 inactivation disables mitotic checkpoint surveillance at anaphase onset in human cells. Preventing cyclin B1 proteolysis at the time of sister chromatid disjunction destabilizes kinetochore-microtubule attachments and triggers the engagement of the mitotic checkpoint. As a consequence, mitotic checkpoint proteins accumulate at anaphase kinetochores, the APC/CCdc20 is inhibited, and securin reaccumulates. Conversely, acute pharmacological inhibition of Cdk1 abrogates the engagement and maintenance of the mitotic checkpoint upon microtubule depolymerization. We propose that the simultaneous destruction of securin and cyclin B elicited by the APC/CCdc20 couples chromosome segregation to the dissolution of attachment monitoring mechanisms during mitotic exit

Surviving streptococcal toxic shock syndrome: a case report

Streptococcal toxic shock syndrome and associated myositis caused by group A beta-hemolytic streptococcus pyogenes generally have a poor outcome despite aggressive operative treatment. Frequently the diagnosis is missed initially as the clinical features are non-specific. The progression to a toxic state is rapid and unless definitive treatment measures are initiated early, the end result can be catastrophic. We report a previously healthy patient who had features of toxic shock syndrome due to alpha haemolytic (viridans) streptococcus mitis which was treated successfully with antibiotics, aggressive intensive care support including the use of a 'sepsis care bundle', monitoring and continuous multidisciplinary review. Life and limb threatening emergencies due to streptococcus mitis in an immune-competent person are rare and to our knowledge, have not previously been described in the English scientific literature. Successful outcome is possible provided a high degree of suspicion is maintained and the patient is intensively monitored

Simulations of the Static Friction Due to Adsorbed Molecules

The static friction between crystalline surfaces separated by a molecularly thin layer of adsorbed molecules is calculated using molecular dynamics simulations. These molecules naturally lead to a finite static friction that is consistent with macroscopic friction laws. Crystalline alignment, sliding direction, and the number of adsorbed molecules are not controlled in most experiments and are shown to have little effect on the friction. Temperature, molecular geometry and interaction potentials can have larger effects on friction. The observed trends in friction can be understood in terms of a simple hard sphere model.Comment: 13 pages, 13 figure

Capture of Escherichia coli O157:H7 Using Immunomagnetic Beads of Different Size and Antibody Conjugating Chemistry

Immunomagnetic beads (IMB) were synthesized using anti-Escherichia coli O157 antibodies and magnetic beads of two different sizes (1 μm and 2.6 to 2.8 μm) that contained a streptavidin coating, activated carboxyl groups or tosylated surfaces. The synthesized IMB, together with a commercially available IMB, were used to capture different strains of E. coli O157:H7 and E. coli O157:NM. The E. coli capture was measured by the time resolved fluorescence (TRF) intensity using a sandwich assay which we have previously demonstrated of having a sensitivity of 1 CFU/g after 4.5 hour enrichment [1]. The analyses of measured TRF intensity and determined antibody surface concentration indicated that larger beads provided higher response signals than smaller beads and were more effective in capturing the target of interest in pure culture and ground beef. In addition, while each type of IMB showed different favorable capture of E. coli O157:H7, streptavidin-coated IMB elicited the highest response, on average. Streptavidin-coated IMB also provided an economic benefit, costing less than $0.50 per assay. The results could be used to guide the proper choice of IMB for applications in developing detection processes for E. coli O157:H7