Involvement of proteasome activation

Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by a progressive decline in a variety of cognitive and non-cognitive functions. The amyloid beta protein cascade hypothesis places the formation of amyloid beta protein aggregates on the first position in the complex pathological cascade leading to neurodegeneration, and therefore AD might be considered to be a protein-misfolding disease. The Ubiquitin Proteasome System (UPS), being the primary protein degradation mechanism with a fundamental role in the maintenance of proteostasis, has been identified as a putative therapeutic target to delay and/or to decelerate the progression of neurodegenerative disorders that are characterized by accumulated/aggregated proteins. The purpose of this study was to test if the activation of proteasome in vivo can alleviate AD pathology. Specifically by using two compounds with complementary modes of proteasome activation and documented antioxidant and redox regulating properties in the 5xFAD transgenic mice model of AD, we ameliorated a number of AD related deficits. Shortly after proteasome activation we detected significantly reduced amyloid-beta load correlated with improved motor functions, reduced anxiety and frailty level. Essentially, to our knowledge this is the first report to demonstrate a dual activation of the proteasome and its downstream effects. In conclusion, these findings open up new directions for future therapeutic potential of proteasome-mediated proteolysis enhancement.publishersversionpublishe

Sexual Dimorphism in Healthy Aging and Mild Cognitive Impairment: A DTI Study

Previous PET and MRI studies have indicated that the degree to which pathology translates into clinical symptoms is strongly dependent on sex with women more likely to express pathology as a diagnosis of AD, whereas men are more resistant to clinical symptoms in the face of the same degree of pathology. Here we use DTI to investigate the difference between male and female white matter tracts in healthy older participants (24 women, 16 men) and participants with mild cognitive impairment (21 women, 12 men). Differences between control and MCI participants were found in fractional anisotropy (FA), radial diffusion (DR), axial diffusion (DA) and mean diffusion (MD). A significant main effect of sex was also reported for FA, MD and DR indices, with male control and male MCI participants having significantly more microstructural damage than their female counterparts. There was no sex by diagnosis interaction. Male MCIs also had significantly less normalised grey matter (GM) volume than female MCIs. However, in terms of absolute brain volume, male controls had significantly more brain volume than female controls. Normalised GM and WM volumes were found to decrease significantly with age with no age by sex interaction. Overall, these data suggest that the same degree of cognitive impairment is associated with greater structural damage in men compared with women

Transcriptome Analysis of Synaptoneurosomes Identifies Neuroplasticity Genes Overexpressed in Incipient Alzheimer's Disease

In Alzheimer's disease (AD), early deficits in learning and memory are a consequence of synaptic modification induced by toxic beta-amyloid oligomers (oAβ). To identify immediate molecular targets downstream of oAβ binding, we prepared synaptoneurosomes from prefrontal cortex of control and incipient AD (IAD) patients, and isolated mRNAs for comparison of gene expression. This novel approach concentrates synaptic mRNA, thereby increasing the ratio of synaptic to somal mRNA and allowing discrimination of expression changes in synaptically localized genes. In IAD patients, global measures of cognition declined with increasing levels of dimeric Aβ (dAβ). These patients also showed increased expression of neuroplasticity related genes, many encoding 3′UTR consensus sequences that regulate translation in the synapse. An increase in mRNA encoding the GluR2 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) was paralleled by elevated expression of the corresponding protein in IAD. These results imply a functional impact on synaptic transmission as GluR2, if inserted, maintains the receptors in a low conductance state. Some overexpressed genes may induce early deficits in cognition and others compensatory mechanisms, providing targets for intervention to moderate the response to dAβ

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Performance of hydroponically cultivated geranium and common verbena under salinity and high electrical conductivity levels

Abiotic factors in nutrient solutions (NSs), such as salinity and high electrical conductivity (EC), may adversely alter plant growth and crop performance. However, there are medici-nal/aromatic plants which can not only withstand these adverse conditions, but which can also increase their productivity or even enhance their quality in such conditions. As fresh water sources suitable for irrigation are becoming more and more limited, the use of low-quality water sources and hydroponic growing systems have been suggested as the main alternatives. Towards that direction, this study aims to evaluate the effect of high EC levels in NSs on geranium (Pelargonium graveolens L’Hér.) and common verbena (Verbena officinallis L.) plants cultivated in a soilless (perlite) hydroponics system. Plants were irrigated with a full nutrient solution of EC 2.1 dS m−1 and pH 5.8 until they reached a uniform size. Then, three treatments were applied, namely: (a) a control treatment with an EC of 2.1 dS m−1 in the NS, (b) a high-salinity NS created by adding 75 mM of NaCl (EC under 8.5 dS m−1) and (c) a concentrated NS with an EC of 8.5 dS m−1. In pelargonium, high salinity decreased the total phenolic and total flavonoid contents; antioxidant capacity; N, K, Mg and P content; as well as chlorophyll fluorescence, compared to the control treatment. On the other hand, increased salinity levels increased the Na and Ca content and stomatal resistance. In common verbena, salinity decreased total phenolic content and chlorophyll fluorescence but increased total flavonoid content; antioxidants; leaf K, P, Na, Cu and Zn content; and stomatal resistance, compared to the control. In both species, high EC did not affect polyphenols, flavonoids or antioxidants, whereas it increased stomatal resistance and nutrient accumulation in the leaves, and decreased chlorophyll fluorescence compared to the control treatment. Damage indices, indicated by lipid peroxidation, hydrogen peroxide production and the elevation of enzymes’ antioxidant activities, were evidenced in both saline-and high-EC-treated plants. In conclusion, despite having the same EC levels in the nutrient solution, it seems that ionic stress caused by high mineral concentrations in the nutrient solution had less severe effects on the tested plants than the relevant osmotic stress caused by high salinity due to the addition of NaCl in the nutrient solution. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Nonce@Once: A single-trace EM side channel attack on several constant-time elliptic curve implementations in mobile platforms

We present the first side-channel attack on fullfledged smartphones that recovers the elliptic curve secret scalar from the electromagnetic signal that corresponds to a single scalar-by-point multiplication in current versions of Libgcrypt, OpenSSL, HACL* and curve25519-donna. To avoid leaking information via side channels, these implementations follow the recommendations of RFC 7748 and use a constant-time conditional swap operation. Our attack targets signal differences created by systematic changes in operand values during this conditional swap operation. We deploy the attack, using low-cost equipment (<$800), against two Android-based mobile phones and against a Linux-based IoT development board. We repeat the attack 100 times, each time with a different scalar, on each device. In all of the implementations considered in this work, our attack successfully recovers the full secret key within seconds. To mitigate the attack we suggest randomizing the exclusive-or mask in the conditional swap operation. We show that this countermeasure is effective in preventing this and similar attacks.Monjur Alam, Baki Yilmaz, Frank Werner, Niels Samwel, Alenka Zajic, Daniel Genkin, Yuval Yarom, Milos Prvulovi