Histone Deacetylase Inhibitors as Multitarget Ligands: New Players in Alzheimer's Disease Drug Discovery?

Histone deacetylase inhibitors (HDACIs) are responsible for controlling gene expression by modulating the acetylation status of histone proteins. Furthermore, they modulate the activity of cytoplasmic non-histone proteins. Due to the involvement of HDACs in neurodevelopment, memory formation, and cognitive processes, HDACIs have been suggested as innovative agents for the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). Given their mechanisms of action and the complex nature of AD, HDACIs have been proposed for the design of novel multitarget ligands (MTLs). To this aim, the fragment responsible for HDAC inhibition has been coupled with other structures that are able to provide additional biological actions, such as antioxidant activity or the inhibition of phosphodiesterase 5, transglutaminase 2, and glycogen synthase kinase 3β. Herein we discuss recent efforts to design HDACI-based MTLs as potential disease-modifying entities.     

Synthesis of Spiro[piperidine‐3,3′‐oxindoles] via Gold(I)‐Catalyzed Dearomatization of N‐Propargyl‐ and N‐Homoallenyl‐2‐bromotryptamines

N‐Propargyl‐ and N‐homoallenyl‐2‐bromo‐β‐tryptamines undergo gold(I)‐catalyzed dearomatizing cyclizations to afford 2‐bromospiroindolenines that are in situ hydrolyzed to furnish spirooxindoles in a one‐pot process. Tryptophane derivatives (R²=CO₂Et) led upon cyclization to chiral spirooxindoles in excellent diastereoselectivities.

     

Effects of Oxide Content on the Glass-Forming Ability of the Ga2S3-Na2S System

Gallium–sodium–sulfide glasses have been shown to be the most promising host for the 1.3 μm fiber optic amplifier so far. However, the current study has revealed that the formation of stable glasses in this system relies on the existence of a certain amount of oxide in the composition. A glass-forming region was identified when 3 mol% Ga₂O₃ was introduced into the melts. Both bulk crystallization and surface crystallization can take place in this system. The thermal behavior of the glasses obtained was studied by DTA and characteristic infrared and UV/visible transmission spectra are presented. The current results are discussed and compared with those previously reported.     

The GAUGAA Motif Is Responsible for the Binding between circSMARCA5 and SRSF1 and Related Downstream Effects on Glioblastoma Multiforme Cell Migration and Angiogenic Potential

Circular RNAs (circRNAs) are a large class of RNAs with regulatory functions within cells. We recently showed that circSMARCA5 is a tumor suppressor in glioblastoma multiforme (GBM) and acts as a decoy for Serine and Arginine Rich Splicing Factor 1 (SRSF1) through six predicted binding sites (BSs). Here we characterized RNA motifs functionally involved in the interaction between circSMARCA5 and SRSF1. Three different circSMARCA5 molecules (Mut1, Mut2, Mut3), each mutated in two predicted SRSF1 BSs at once, were obtained through PCR-based replacement of wild-type (WT) BS sequences and cloned in three independent pcDNA3 vectors. Mut1 significantly decreased its capability to interact with SRSF1 as compared to WT, based on the RNA immunoprecipitation assay. In silico analysis through the “Find Individual Motif Occurrences” (FIMO) algorithm showed GAUGAA as an experimentally validated SRSF1 binding motif significantly overrepresented within both predicted SRSF1 BSs mutated in Mut1 (q-value = 0.0011). U87MG and CAS-1, transfected with Mut1, significantly increased their migration with respect to controls transfected with WT, as revealed by the cell exclusion zone assay. Immortalized human brain microvascular endothelial cells (IM-HBMEC) exposed to conditioned medium (CM) harvested from U87MG and CAS-1 transfected with Mut1 significantly sprouted more than those treated with CM harvested from U87MG and CAS-1 transfected with WT, as shown by the tube formation assay. qRT-PCR showed that the intracellular pro- to anti-angiogenic Vascular Endothelial Growth Factor A (VEGFA) mRNA isoform ratio and the amount of total VEGFA mRNA secreted in CM significantly increased in Mut1-transfected CAS-1 as compared to controls transfected with WT. Our data suggest that GAUGAA is the RNA motif responsible for the interaction between circSMARCA5 and SRSF1 as well as for the circSMARCA5-mediated control of GBM cell migration and angiogenic potential.     

SOCIO-ECONOMIC ASPECTS OF THE AUSTRIAN 200 kWp-PHOTOVOLTAIC-ROOFTOP PROGRAMME

Between 1992 and 1994 a 200 kWp-rooftop programme to promote small grid-connected Photovoltaic (PV) systems was conducted in Austria. Within this programme about 100 PV systems with an average capacity of 2.28 kWp were installed. This paper investigates the socio-economic aspects of this programme and the prospects for a further dissemination of this technology. The major conclusions of this investigation are as follows: (1) The motives to invest in a PV system are: (i) environmental protection; (ii) an alternative to nuclear power; (iii) technical interest. Yet, it is also important that the public supports this purchase by means providing subsidies. (2) The purchase of a PV system leads to different changes in consumer behaviour. Consumers with low initial consumption increased their electricity demand slightly, while the majority of consumers with high initial electricity demand saved electricity. (3) The financial incentives in the programme were not optimally designed. With the same amount of total subsidies it would have been possible to promote more PV systems. (4) The key factors for a further dissemination of PV systems are: (i) financial incentives; (ii) a reduction of the investment costs; (iii) increase in reliability; (iv) distribution of information; (v) enhancement of environmental awareness.     

A short term −12° head down tilt does not mimic microgravity in terms of human gonadal function

A significant reversible decrease in testosterone (T) has been associated with microgravity in male rodents and humans. Urinary T excretion increases in primates under hypergravity. Hypogonadism is somehow related to abnormally high levels of leptin (L), a hormone produced by the adipose tissue which has been found to increase under microgravity simulation conditions like head down bed rest (HDBR). The aim of this study was to assess hemodynamic and pituitary-adrenal and -gonadal adaptation to an acute HDBR test to be eventually used on a routine basis to get better prepared to next space flights. The Authors performed a 1 hour ?12° HDBR in 6 male and 6 female volunteers who underwent heart rate and blood pressure measurement together with a blood draw three times at 30 min intervals from the start to the end of the test for L, T, estradiol (E₂), LH, androstenedione (A), cortisol (F), ACTH. 12 age- and sexmatched control subjects followed the same protocol except for keeping the sitting position all the time. According to the ANOVA for repeated measures, no changes occurred in L, T, E₂ or LH whereas A, F and ACTH significantly decreased independently of gender. During HDBR systolic blood pressure decreased in both genders, diastolic blood pressure decreased significantly only in men and HR showed a more clear-cut decrease in women than in men. As a conclusion, such an acute steep-slope HDBR protocol may be efficiently used to testing immediate individual haemodynamic or adrenal response to microgravity but is not suitable for studies concerning gonadal adaptation.     

Upregulation of Anti-Oxidative Stress Response Improves Metabolic Changes in L-Selectin-Deficient Mice but Does Not Prevent NAFLD Progression or Fecal Microbiota Shifts

(1) Background: Non-alcoholic fatty liver disease (NAFLD) is a growing global health problem. NAFLD progression involves a complex interplay of imbalanced inflammatory cell populations and inflammatory signals such as reactive oxygen species and cytokines. These signals can derive from the liver itself but also from adipose tissue or be mediated via changes in the gut microbiome. We analyzed the effects of a simultaneous migration blockade caused by L-selectin-deficiency and an enhancement of the anti-oxidative stress response triggered by hepatocytic Kelch-like ECH-associated protein 1 (Keap1) deletion on NAFLD progression. (2) Methods: L-selectin-deficient mice (Lsel^−/−Keap1^flx/flx) and littermates with selective hepatic Keap1 deletion (Lsel^−/−Keap1^Δhepa) were compared in a 24-week Western-style diet (WD) model. (3) Results: Lsel^−/−Keap1^Δhepa mice exhibited increased expression of erythroid 2-related factor 2 (Nrf2) target genes in the liver, decreased body weight, reduced epidydimal white adipose tissue with decreased immune cell frequencies, and improved glucose response when compared to their Lsel^−/−Keap1^flx/flx littermates. Although WD feeding caused drastic changes in fecal microbiota profiles with decreased microbial diversity, no genotype-dependent shifts were observed. (4) Conclusions: Upregulation of the anti-oxidative stress response improves metabolic changes in L-selectin-deficient mice but does not prevent NAFLD progression and shifts in the gut microbiota.     

What predicts psychological resilience after disaster? The role of demographics, resources, and life stress.

A growing body of evidence suggests that most adults exposed to potentially traumatic events are resilient. However, research on the factors that may promote or deter adult resilience has been limited. This study examined patterns of association between resilience and various sociocontextual factors. The authors used data from a random-digit-dial phone survey (N = 2,752) conducted in the New York City area after the September 11, 2001, terrorist attack. Resilience was defined as having 1 or 0 posttraumatic stress disorder symptoms and as being associated with low levels of depression and substance use. Multivariate analyses indicated that the prevalence of resilience was uniquely predicted by participant gender, age, race/ethnicity, education, level of trauma exposure, income change, social support, frequency of chronic disease, and recent and past life stressors. Implications for future research and intervention are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

“Okay,My Rant is Over”: The Language of Emotion in Computer-Mediated Communication

Even when instructors take steps to mitigate conflict between students, online discussions are likely to be more emotional than face-to-face discussions, and student posts frequently bear characteristics of ranting. This paper uses a model from the field of psycholinguistics to identify linguistic features that writers use to communicate emotion in CMC to substitute for the nonverbal emotional cues that speakers and listeners rely on in face-to-face conversation. Our analysis of the online forum for a course called Presidential Election Rhetoric illustrates not only that students use linguistic features to express emotion but also that they transmit emotion to one another through the use of these features. Additionally, we suggest that students’ unfamiliarity expressing emotion subtly and accurately using linguistic features contributes to the quality of ranting in CMC. Finally, we recommend specific strategies to help students further hone their skills at expressing and perceiving emotion in CMC.