Survivin Mutant Protects Differentiated Dopaminergic SK-N-SH Cells Against Oxidative Stress

Oxidative stress is due to an imbalance of antioxidant/pro-oxidant homeostasis and is associated with the progression of several neurological diseases, including Parkinson's and Alzheimer's disease and amyotrophic lateral sclerosis. Furthermore, oxidative stress is responsible for the neuronal loss and dysfunction associated with disease pathogenesis. Survivin is a member of the inhibitors of the apoptosis (IAP) family of proteins, but its neuroprotective effects have not been studied. Here, we demonstrate that SurR9-C84A, a survivin mutant, has neuroprotective effects against H2O2-induced neurotoxicity. Our results show that H2O2 toxicity is associated with an increase in cell death, mitochondrial membrane depolarisation, and the expression of cyclin D1 and caspases 9 and 3. In addition, pre-treatment with SurR9-C84A reduces cell death by decreasing both the level of mitochondrial depolarisation and the expression of cyclin D1 and caspases 9 and 3. We further show that SurR9-C84A increases the antioxidant activity of GSH-peroxidase and catalase, and effectively counteracts oxidant activity following exposure to H2O2. These results suggest for the first time that SurR9-C84A is a promising treatment to protect neuronal cells against H2O2-induced neurotoxicity

APOE ε4 lowers age at onset and is a high risk factor for Alzheimer's disease; A case control study from central Norway

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to analyze factors influencing the risk and timing of Alzheimer's disease (AD) in central Norway. The <it>APOE </it>ε4 allele is the only consistently identified risk factor for late onset Alzheimer's disease (LOAD). We have described the allele frequencies of the apolipoprotein E gene (<it>APOE</it>) in a large population of patients with AD compared to the frequencies in a cognitively-normal control group, and estimated the effect of the <it>APOE </it>ε4 allele on the risk and the age at onset of AD in this population.</p> <p>Methods</p> <p>376 patients diagnosed with AD and 561 cognitively-normal control individuals with no known first degree relatives with dementia were genotyped for the <it>APOE </it>alleles. Allele frequencies and genotypes in patients and control individuals were compared. Odds Ratio for developing AD in different genotypes was calculated.</p> <p>Results</p> <p>Odds Ratio (OR) for developing AD was significantly increased in carriers of the <it>APOE </it>ε4 allele compared to individuals with the <it>APOE </it>ε3/ε3 genotype. Individuals carrying <it>APOE </it>ε4/ε4 had OR of 12.9 for developing AD, while carriers of <it>APOE </it>ε2/ε4 and <it>APOE </it>ε3/ε4 had OR of 3.2 and 4.2 respectively. The effect of the <it>APOE </it>ε4 allele was weaker with increasing age. Carrying the <it>APOE </it>ε2 allele showed no significant protective effect against AD and did not influence age at onset of the disease. Onset in LOAD patients was significantly reduced in a dose dependent manner from 78.4 years in patients without the <it>APOE </it>ε4 allele, to 75.3 in carriers of one <it>APOE </it>ε4 allele and 72.9 in carriers of two <it>APOE </it>ε4 alleles. Age at onset in early onset AD (EOAD) was not influenced by <it>APOE </it>ε4 alleles.</p> <p>Conclusion</p> <p><it>APOE </it>ε4 is a very strong risk factor for AD in the population of central Norway, and lowers age at onset of LOAD significantly.</p

Inflammatory biomarkers in Alzheimer&apos;s disease plasma

Introduction: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a \u201cHoly Grail\u201d of AD research and intensively sought; however, there are no well-established plasma markers. Methods: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. Results: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APO\u3b54 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). Discussion: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

The Shadow Rate of Interest, Macroeconomic Trends, and Time{Varying Uncertainty

Poster Session A (Posters will be up throughout the conference

Are Long-Run Inflation Expectations Anchored More Firmly in the Euro Area than in the United States?

This paper compares the recent evolution of long-run inflation expectations in the euro area and the United States, using evidence from financial markets and surveys of professional forecasters. Survey data indicate that long-run inflation expectations are reasonably well-anchored in both economies, but also reveal substantially greater dispersion across forecasters’ long-horizon projections of U.S. inflation. Daily data on inflation swaps and nominal-indexed bond spreads - which gauge compensation for expected inflation and inflation risk - also suggest that long-run inflation expectations are more firmly anchored in the euro area than in the United States. In particular, surprises in macroeconomic data releases have significant effects on U.S. forward inflation compensation, even at long horizons, whereas macroeconomic news only influences euro area inflation compensation at short horizons.central bank communication; ECB; euro-area inflation; inflation compensation

Are long-run inflation expectations anchored more firmly in the Euro area than in the United States?

This paper compares the recent evolution of long-run inflation expectations in the euro area and the United States, using evidence from financial markets and surveys of professional forecasters. Survey data indicate that long-run inflation expectations are reasonably well-anchored in both economies, but also reveal substantially greater dispersion across forecasters' long-horizon projections of U.S. inflation. Daily data on inflation swaps and nominal-indexed bond spreads--which gauge compensation for expected inflation and inflation risk--also suggest that long-run inflation expectations are more firmly anchored in the euro area than in the United States. In particular, surprises in macroeconomic data releases have significant effects on U.S. forward inflation compensation, even at long horizons, whereas macroeconomic news only influences euro area inflation compensation at short horizons.Inflation (Finance) - United States ; Inflation (Finance) - Euro area ; Banks and banking, Central

Are the effects of a non-drug multimodal activation therapy of dementia sustainable? Follow-up study 10 months after completion of a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Little is known about the long-term success of non-drug therapies for treating dementia, especially whether the effects are sustained after therapy ends. Here, we examined the effects of a one-year multimodal therapy 10 months after patients completed the therapy.</p> <p>Methods</p> <p>This randomised, controlled, single-blind, longitudinal trial involved 61 patients (catamnesis: n = 52) with primary degenerative dementia in five nursing homes in Bavaria, Germany. The highly standardised intervention, MAKS, consisted of motor stimulation, practice of activities of daily living (ADLs), and cognitive stimulation. Each group of 10 patients was treated for 2 h, 6 days a week for 12 months. Control patients received standard nursing home care. At baseline, at the end of therapy (month 12), and 10 months thereafter (month 22), cognitive functioning was assessed using the cognitive subscale of the Alzheimer’s Disease Assessment Scale, and the ability to perform ADLs was assessed using the Erlangen Test of Activities of Daily Living.</p> <p>Results</p> <p>During the therapy phase, the MAKS patients maintained their cognitive function and ability to carry out ADLs. After the end of therapy, both the control and the MAKS groups deteriorated in both their cognitive function (control, p = 0.02; MAKS, p < 0.001) and their ability to carry out ADLs (control, p < 0.001; MAKS, p = 0.001). However, in a confound-adjusted multiple regression model, the ability of the MAKS group to perform ADLs remained significantly higher than that of the control group even 10 months after the end of therapy (H₀: β_MAKS + β_{MAKS month 22} = 0; χ² = 3.8568, p = 0.0496). Cohen’s d for the difference between the two groups in ADLs and cognitive abilities 10 months after the end of therapy was 0.40 and 0.22, respectively.</p> <p>Conclusions</p> <p>A multimodal non-drug therapy of dementia resulted in stabilisation of the ability to perform ADLs, even beyond the end of therapy. To prevent functional decline for as long as possible, therapy should be performed continuously until the benefit for the patient ends. Follow-up studies on larger numbers of patients are needed to definitively confirm these results.</p> <p>Trial registration</p> <p><url>http://www.isrctn.com</url> Identifier: ISRCTN87391496</p