Parkinson's disease (PD) is a neurodegenerative disorder characterized by a combination of motor symptoms. We identified two functional single nucleotide polymorphisms in the glycogen synthase ...kinase‐3β gene (GSK3B). A promoter single nucleotide polymorphism (rs334558) is associated with transcriptional strength in vitro in which the T allele has greater activity. An intronic single nucleotide polymorphism (rs6438552) regulates selection of splice acceptor sites in vitro. The T allele is associated with altered splicing in lymphocytes and increased levels of GSK3B transcripts that lack exons 9 and 11 (GSKΔexon9+11). Increased levels of GSKΔexon9+11 correlated with enhanced phosphorylation of its substrate, Tau. In a comparison of PD and control brains, there was increased in frequency of T allele (rs6438552) and corresponding increase in GSKΔexon9+11 and Tau phosphorylation in PD brains. Conditional logistic regression indicated gene–gene interaction between T/T genotype of rs334558 and H1/H1 haplotype of microtubule‐associated protein Tau (MAPT) gene (p = 0.009). There was association between a haplotype (T alleles of both GSK3B polymorphisms) and disease risk after stratification by Tau haplotypes ((H1/H2+H2/H2 individuals: odds ratio, 1.64; p = 0.007; (H1/H1 individuals: odds ratio, 0.68; p < 0.001). Ours results suggest GSK3B polymorphisms alter transcription and splicing and interact with Tau haplotypes to modify disease risk in PD. Ann Neurol 2005;58:829–839
Hyperglycemia-induced oxidative stress plays a central role in the development of diabetic myocardial complications. Adiponectin (APN), an adipokine with anti-diabetic and anti-ischemic effects, is ...decreased in diabetes. It is unknown whether or not antioxidant treatment with N-acetylcysteine (NAC) and/or allopurinol (ALP) can attenuate APN deficiency and myocardial ischemia reperfusion (MI/R) injury in the early stage of diabetes.
Control or streptozotocin (STZ)-induced diabetic rats were either untreated (C, D) or treated with NAC (1.5 g/kg/day) or ALP (100 mg/kg/day) or their combination for four weeks starting one week after STZ injection. Plasma and cardiac biochemical parameters were measured after the completion of treatment, and the rats were subjected to MI/R by occluding the left anterior descending artery for 30 min followed by 2 h reperfusion. Plasma and cardiac APN levels were decreased in diabetic rats accompanied by decreased cardiac APN receptor 2 (AdipoR2), reduced phosphorylation of Akt, signal transducer and activator of transcription 3 (STAT3) and endothelial nitric oxide synthase (eNOS) but increased IL-6 and TNF-α (all P<0.05 vs. C). NAC but not ALP increased cardiac APN concentrations and AdipoR2 expression in diabetic rats. ALP enhanced the effects of NAC in restoring cardiac AdipoR2 and phosphorylation of Akt, STAT3 and eNOS in diabetic rats. Further, NAC and ALP, respectively, decreased postischemic myocardial infarct size and creatinine kinase-MB (CK-MB) release in diabetic rats, while their combination conferred synergistic protective effects. In addition, exposure of cultured rat cardiomyocytes to high glucose resulted in significant reduction of cardiomyocyte APN concentration and AdipoR2 protein expression. APN supplementation restored high glucose induced AdipoR2 reduction in cardiomyocytes.
NAC and ALP synergistically restore myocardial APN and AdipoR2 mediated eNOS activation. This may represent the mechanism through which NAC and ALP combination greatly reduces MI/R injury in early diabetic rats.
Understanding how human genetics influence infectious disease susceptibility offers the opportunity for new insights into pathogenesis, potential drug targets, risk stratification, response to ...therapy and vaccination. As new infectious diseases continue to emerge, together with growing levels of antimicrobial resistance and an increasing awareness of substantial differences between populations in genetic associations, the need for such work is expanding. In this Review, we illustrate how our understanding of the host-pathogen relationship is advancing through holistic approaches, describing current strategies to investigate the role of host genetic variation in established and emerging infections, including COVID-19, the need for wider application to diverse global populations mirroring the burden of disease, the impact of pathogen and vector genetic diversity and a broad array of immune and inflammation phenotypes that can be mapped as traits in health and disease. Insights from study of inborn errors of immunity and multi-omics profiling together with developments in analytical methods are further advancing our knowledge of this important area.
Second harmonic generation (SHG) was used to selectively probe DNA-drug interactions without the need for chemical labels or invasive detection methods. In particular, the binding constant of the ...anticancer drug daunomycin to a recognition triplet sequence in a 33-mer of double stranded DNA was determined. The SHG method, which is interface selective, probed the binding of daunomycin to DNA that was tethered to the surface of colloidal microparticles suspended in aqueous solution. Probing biomolecule coated colloids is expected to yield larger SH signals and provides experimental flexibility as compared to experiments performed at planar interfaces. The change in SHG intensity as daunomycin was added to the microparticle solution was fit to a Langmuir binding model, which yielded an equilibrium constant of 2.3 (±0.7) × 10(5) M(-1); the corresponding Gibbs free energy change at 20 °C is -7.2 ± 0.2 kcal/mol. Control experiments established that daunomycin preferentially binds to DNA at the recognition sequence. The equilibrium was found to be unaffected by the presence of free DNA in solution, and hyper-Rayleigh scattering from bulk molecules did not change with increasing daunomycin concentration. The extracted equilibrium constants are in agreement with the range of reported values found in the literature.
Ferritin, an iron storage and regulation protein, has been associated with Alzheimer's disease (AD); however, it has not been investigated in preclinical AD, detected by neocortical amyloid-β load ...(NAL), before cognitive impairment. Cross-sectional analyses were carried out for plasma and serum ferritin in participants in the Kerr Anglican Retirement Village Initiative in Aging Health cohort. Subjects were aged 65-90 years and were categorized into high and low NAL groups via positron emission tomography using a standard uptake value ratio cutoff=1.35. Ferritin was significantly elevated in participants with high NAL compared with those with low NAL, adjusted for covariates age, sex, apolipoprotein E ɛ4 carriage and levels of C-reactive protein (an inflammation marker). Ferritin was also observed to correlate positively with NAL. A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve (AUC)=0.766), but was outperformed when plasma ferritin was added to the base model (AUC=0.810), such that at 75% sensitivity, the specificity increased from 62 to 71% on adding ferritin to the base model, indicating that ferritin is a statistically significant additional predictor of NAL over and above the base model. However, ferritin's contribution alone is relatively minor compared with the base model. The current findings suggest that impaired iron mobilization is an early event in AD pathogenesis. Observations from the present study highlight ferritin's potential to contribute to a blood biomarker panel for preclinical AD.
Microscopic imaging techniques to visualize cellular behaviors in their natural environment play a pivotal role in biomedical research. Here, we review how recent technical advances in intravital ...microscopy have enabled unprecedented access to cellular physiology in various organs of mice in normal and diseased states.
Alzheimer's disease (AD) and Parkinson's disease (PD) are two common neurodegenerative diseases that result in the progressive damage or death of neurons. Environmental agents have the potential to ...damage the developing and mature nervous system, resulting in neurodegenerative diseases. Heritable changes in gene expression that do not involve coding sequence modifications are referred to as 'epigenetic'. These modifications include DNA methylation and downstream modification of histones. Environmental factors, including heavy metals and dietary folate intake, perturb neurodegenerative genes by epigenetic means, leading to altered gene expression and late-onset neurodegenerative diseases. Research into the genetic control of DNA methylation indicates an allelic skewing in a significant proportion of genes. This phenomenon may determine how an individual's genetic makeup can alter the effect an environmental factor has on their risk of developing neurodegeneration. Finally, preliminary evidence using cell culture and transgenic animal models suggests that whole classes of pan-epigenetic modifiers will have significant protective effects against common neurodegenerative diseases.
The synthesis and performance of (La0.75Sr0.25)(Cr0.5Mn0.5)O3/Y2O3-ZrO2 (LSCM/YSZ) composites are investigated as alternative anodes for the direct utilization of methane (i.e., natural gas) in solid ...oxide fuel cells. Addition of YSZ phase greatly improves the adhesion and reduces the electrode polarization resistance of the LSCM/YSZ composite anodes. LSCM/YSZ composite anodes show reasonably good performance for the methane oxidation reaction in wet CH4 and the best electrode performance was achieved for the composite with LSCM contents of 50-60 wt.% with polarization resistances of 2-3 Omega cm2 in 97% CH4/3% H2O at 850 deg C. The electrode impedance for the methane oxidation in wet CH4 on the LSCM/YSZ composite anodes was characterized by three separable arcs and the electrode behavior could be explained based on the ALS model for the reaction on the MIEC electrode. The results indicate that electrocatalytic activity of the LSCM/YSZ composite anodes for the methane oxidation is likely limited by the oxygen vacancy diffusion in the substituted lanthanum chromite-based materials.
Executive functions are amongst the most heritable cognitive traits with twin studies indicating a strong genetic origin. However genes associated with this domain are unknown. Our research into the ...neurodevelopmental disorder Williams-Beuren syndrome (WBS) has identified a gene within the causative recurrent 1.5/1.6 Mb heterozygous microdeletion on chromosome 7q11.23, which may be involved in executive functioning. Comparative genome array screening of 55 WBS patients revealed a larger ∼1.8 Mb microdeletion in 18% of cases, which results in the loss of an additional gene, the transcription factor GTF2IRD2. The GTF gene family of transcription factors (GTF2I, GTF2IRD1 and GTF2IRD2) are all highly expressed in the brain, and GTF2I and GTF2IRD1 are involved in the pathogenesis of the cognitive and behavioural phenotypes associated with WBS. A multi-level analysis of cognitive, behavioural and psychological functioning in WBS patients showed that those with slightly larger deletions encompassing GTF2IRD2 were significantly more cognitively impaired in the areas of spatial functioning, social reasoning, and cognitive flexibility (a form of executive functioning). They also displayed significantly more obsessions and externalizing behaviours, a likely manifestation of poor cognitive flexibility and executive dysfunction. We provide the first evidence for a role for GTF2IRD2 in higher-level (executive functioning) abilities and highlight the importance of integrating detailed molecular characterisation of patients with comprehensive neuropsychological profiling to uncover additional genotype-phenotype correlations. The identification of specific genes which contribute to executive function has important neuropsychological implications in the treatment of patients with conditions like WBS, and will allow further studies into their mechanism of action.
A method is described in which the interference of radiated second-harmonic electric fields generated by a pair of oriented molecules intercalated into double-stranded DNA is controlled and measured. ...The results show that the relative molecular orientation of the two molecules significantly changes the magnitude of the observed second-harmonic generation intensity, which is described by a simple model that accounts for the interferences of the radiated fields. The technique presented shows promise for future experiments investigating structural changes induced by the formation of a DNA—biomolecule complex.
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