Aminkatalyserad asymmetrisk Friedel-Crafts-alkylering

Organokatalytisk asymmetrisk Friedel-Crafts-alkylering av olika aromatiska och heteroaromatiska nukleofiler med α,β-omättade aldehyder och ketoner har visat sig vara en effektiv metod för att syntetisera olika grundstrukturer för viktiga biologiskt aktiva föreningar. Under det senaste årtiondet har forskningen inom detta område gått framåt med stora steg. Det var David W. C. MacMillan som startade utvecklingen av organokatalytisk asymmetrisk F-C-alkylering då han presenterade den LUMO-sänkande iminaktiveringsmekanismen för första gången. Dessutom introducerade han första generationens imidazolidinon vilken visade hög katalytisk aktivitet i alkyleringsreaktioner av pyrroler med enaler. Trots detta fungerade katalysatorn inte vid indolalkylering p.g.a. steriska hinder vilket ledde till att en serie av förbättrade och nya katalysatorer har utvecklats. Andra generationens imidazolidinon och diarylprolinoletrar har alla visat sig vara bra och effektiva alternativ för asymmetriska F-C-alkyleringar av indoler med enaler. Förutom indoler har dessa använts för att katalysera också reaktioner med aniliner, naftoler och furanderivat. Resultaten har varit mycket bra både med avseende på utbyte och enantioselektivitet. En annan typ av katalysatorer som härstammar från de naturligt förekommande cinkona-alkaloiderna har också introducerats. Dessa primära aminer är speciellt användbara i reaktioner där mera sterisk hindrande α,β-omättade ketoner används istället för aldehyder. Resultaten var även i dessa reaktioner bra och riktgivande för vidare forskning. Andra mindre undersökta och använda organokatalysatorer är bl. a. imidazoltioner och (3-metylaziridin-2-yl)-difenylmetanoler. I framtiden kommer organokatalysatorer att användas allt mer i asymmetriska F-C-reaktioner. Resultaten som erhållits så här långt ger möjlighet att kombinera dessa nya billigare alternativ till de tidigare använda dyra instabila metallkomplexen. Detta minskar på användningen av de svårhanterliga toxiska metallföreningarna och gör synteserna miljövänligare. Organo-katalysatorerna är stabila och icke-toxiska vid rumsbetingelser och därmed lätt att använda i alkyleringsreaktioner. Detta är speciellt viktigt vid syntes av läkemedelsderivat och naturprodukter. Detta kommer att vara ett av de viktigaste tillämpningsområdena där organokatalytisk F-C-alkylering används

Evaluation of Chipping Productivity with Five Different Mobile Chippers at Different Forest Sites by a Stochastic Model

It is important to evaluate chipping productivity that often differed according to the timing of observations and varied unexpectedly. A variation in production was the major concern of stakeholders for sustainable forest operation to establish regularly attainable production schedules on many operational levels. The aim of this study was to estimate the variance of chipping productivity by using a stochastic simulation model to achieve the objective evaluation of chipper performances. Chipping operations of five different kinds of mobile chippers, i.e. three smaller and two middle and larger ones in horse powers, were investigated. Probability distributions of material size and feeding time for chipping in a log-normal distribution were estimated. The estimates were made based on chipping operations performed 2000 or 4000 times by mechanical repetitions. Except for the largest chipper, whose observed productivity was 338 loose m3/hr, all of the observed productivities, varying from 18 to 68 loose m3/hr, were located within a two-sided confidential interval whose difference between both ends was 4 to 10 loose m3/hr. The estimates were, generally, reliable with small variances around the median productivity values in the model. By this stochastic model, chipper productivity could be shown objectively, while the accuracy would be improved more by increasing sample size and accurate material size measurement. It was elucidated that the operations followed by chipping should encompass enough volume capacity to provide stable chipping productivity

Dietary Prebiotics and Bioactive Milk Fractions Improve NREM Sleep, Enhance REM Sleep Rebound and Attenuate the Stress-Induced Decrease in Diurnal Temperature and Gut Microbial Alpha Diversity.

Severe, repeated or chronic stress produces negative health outcomes including disruptions of the sleep/wake cycle and gut microbial dysbiosis. Diets rich in prebiotics and glycoproteins impact the gut microbiota and may increase gut microbial species that reduce the impact of stress. This experiment tested the hypothesis that consumption of dietary prebiotics, lactoferrin (Lf) and milk fat globule membrane (MFGM) will reduce the negative physiological impacts of stress. Male F344 rats, postnatal day (PND) 24, received a diet with prebiotics, Lf and MFGM (test) or a calorically matched control diet. Fecal samples were collected on PND 35/70/91 for 16S rRNA sequencing to examine microbial composition and, in a subset of rats; Lactobacillus rhamnosus was measured using selective culture. On PND 59, biotelemetry devices were implanted to record sleep/wake electroencephalographic (EEG). Rats were exposed to an acute stressor (100, 1.5 mA, tail shocks) on PND 87 and recordings continued until PND 94. Test diet, compared to control diet, increased fecal Lactobacillus rhamnosus colony forming units (CFU), facilitated non-rapid eye movement (NREM) sleep consolidation (PND 71/72) and enhanced rapid eye movement (REM) sleep rebound after stressor exposure (PND 87). Rats fed control diet had stress-induced reductions in alpha diversity and diurnal amplitude of temperature, which were attenuated by the test diet (PND 91). Stepwise multiple regression analysis revealed a significant linear relationship between early-life Deferribacteres (PND 35) and longer NREM sleep episodes (PND 71/72). A diet containing prebiotics, Lf and MFGM enhanced sleep quality, which was related to changes in gut bacteria and modulated the impact of stress on sleep, diurnal rhythms and the gut microbiota

Novel Sulfonanilide Inhibitors of SHIP2 Enhance Glucose Uptake into Cultured Myotubes

A series of substituted sulfonanilide analogs were prepared and evaluated as novel potent inhibitors of SH2 domaincontaining inositol polyphosphate 5′-phosphatase 2 (SHIP2). SHIP2 has been shown to be a new attractive target for the treatment of insulin resistance in type 2 diabetes mellitus (T2D), which can lead to life-threatening diabetic kidney disease (DKD). Amongst the synthesized compounds, the two most promising candidates, 10 and 11, inhibited SHIP2 significantly. Additionally, these compounds induced Akt activation in a dose-dependent manner, increased the presence of glucose transporter 4 at the plasma membrane, and enhanced glucose uptake in cultured myotubes in vitro at lower concentrations than metformin, the most widely used antidiabetic drug. These results show that the novel SHIP2 inhibitors have insulin sensitizing capacity and provide prototypes for further drug development for T2D and DKD.Peer reviewe

Associations between Mobility, Cognition, and Brain Structure in Healthy Older Adults.

Mobility limitations lead to a cascade of adverse events in old age, yet the neural and cognitive correlates of mobility performance in older adults remain poorly understood. In a sample of 387 adults (mean age 69.0 ± 5.1 years), we tested the relationship between mobility measures, cognitive assessments, and MRI markers of brain structure. Mobility was assessed in 2007-2009, using gait, balance and chair-stands tests. In 2012-2015, cognitive testing assessed executive function, memory and processing-speed; gray matter volumes (GMV) were examined using voxel-based morphometry, and white matter microstructure was assessed using tract-based spatial statistics of fractional anisotropy, axial diffusivity (AD), and radial diffusivity (RD). All mobility measures were positively associated with processing-speed. Faster walking speed was also correlated with higher executive function, while memory was not associated with any mobility measure. Increased GMV within the cerebellum, basal ganglia, post-central gyrus, and superior parietal lobe was associated with better mobility. In addition, better performance on the chair-stands test was correlated with decreased RD and AD. Overall, our results indicate that, even in non-clinical populations, mobility measures can be sensitive to sub-clinical variance in cognition and brain structures

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

Metformin, the first-line drug to treat type 2 diabetes (T2D), inhibits mitochondrial glycerolphosphate dehydrogenase in the liver to suppress gluconeogenesis. However, the direct target and the underlying mechanisms by which metformin increases glucose uptake in peripheral tissues remain uncharacterized. Lipid phosphatase Src homology 2 domain-containing inositol-5-phosphatase 2 (SHIP2) is upregulated in diabetic rodent models and suppresses insulin signaling by reducing Akt activation, leading to insulin resistance and diminished glucose uptake. Here, we demonstrate that metformin directly binds to and reduces the catalytic activity of the recombinant SHIP2 phosphatase domain in vitro. Metformin inhibits SHIP2 in cultured cells and in skeletal muscle and kidney of db/db mice. In SHIP2-overexpressing myotubes, metformin ameliorates reduced glucose uptake by slowing down glucose transporter 4 endocytosis. SHIP2 overexpression reduces Akt activity and enhances podocyte apoptosis, and both are restored to normal levels by metformin. SHIP2 activity is elevated in glomeruli of patients with T2D receiving nonmetformin medication, but not in patients receiving metformin, compared with people without diabetes. Furthermore, podocyte loss in kidneys of metformin-treated T2D patients is reduced compared with patients receiving nonmetformin medication. Our data unravel a novel molecular mechanism by which metformin enhances glucose uptake and acts renoprotectively by reducing SHIP2 activity.Polianskyte-Prause, Z., Tolvanen, T. A., Lindfors, S., Dumont, V., Van, M., Wang, H., Dash, S. N., Berg, M., Naams, J.-B., Hautala, L. C., Nisen, H., Mirtti, T., Groop, P.-H., Wahala, K., Tienari, J., Lehtonen, S. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity.Peer reviewe

The dark path to eternal life: Machiavellianism predicts approval of mind upload technology

Mind upload, making a digital copy of one’s brain, is a part of the transhumanistic dream of eternal life and the end of suffering. It is also perceived as a viable route toward artificial general intelligence (AGI). However, AI safety research has alerted to one major risk in creating AGI by mind upload: namely, that mind upload tech-nology could appeal primarily to callous and selfish individuals who then abuse this technology for their personal gain—and, potentially, at a considerable cost to the welfare of humankind. Therefore, it is important to un-derstand whether people’s acceptance of mind upload is associated with pathological and/or antisocial traits. To this end, the present research examined whether individual differences in Dark Triad traits predict attitudes toward mind upload in a sample of 1007 English-speaking adults. A pre-registered structural equation model revealed that Machiavellianism (but not psychopathy) was associated with favorable views about mind upload, both directly and indirectly through utilitarian moral attitudes. These results therefore substantiate the concerns voiced by AI safety researchers—namely, that mind upload technology could be adopted disproportionately by individuals with an antisocial personality.</p

Body Mass Index and Depressive Symptoms: Testing for Adverse and Protective Associations in Two Twin Cohort Studies

Studies have suggested both adverse and protective associations of obesity with depressive symptoms. We examined the contribution of environmental and heritable factors in this association. Participants were same-sex twin pairs from two population-based twin cohort studies, the Older Finnish Twin Cohort (n = 8,215; mean age = 44.1) and the US Midlife Development in the United States (MIDUS; n = 1,105; mean age = 45.1). Body mass index (BMI) was calculated from self-reported height and weight. Depressive symptoms were assessed using Beck's Depression Inventory (BDI; Finnish Twin Cohort), and by negative and positive affect scales (MIDUS). In the Finnish Twin Cohort, higher BMI was associated with higher depressive symptoms in monozygotic (MZ) twins (B = 2.01, 95% CI = 1.0, 3.0) and dizygotic (DZ) twins (B = 1.17, 0.5, 1.9) with BMI &gt;22. This association was observed in within-pair analysis in DZ twins (B = 1.47, CI = 0.4, 2.6) but not in within-pair analysis of MZ twins (B = 0.03, CI = -1.9, 2.0). Consistent with the latter result, a bivariate genetic model indicated that the association between higher BMI and higher depressive symptoms was largely mediated by genetic factors. The results of twin-pair analysis and bivariate genetic model were replicated in the MIDUS sample. These findings suggest an association between obesity and higher depressive symptoms, which is largely explained by shared heritable biological mechanisms.</p

Dedicated plug based closure for large bore access -The MARVEL prospective registry

Objectives To study safety and performance of the MANTA Vascular closure device (VCD) under real world conditions in 10 centers. Background The MANTA is a novel plug-based device for large bore arteriotomy closure. Methods We included all eligible patients who underwent transfemoral large bore percutaneous procedures. Exclusion criteria were per operator's discretion and included severe calcification or marked tortuosity of the access vessel, presence of marked obesity/cachexia or a systolic blood pressure above 180 mmHg. The primary performance endpoint was time to hemostasis. Primary and secondary safety endpoints were major and minor access site related vascular complications up to 30 days, respectively. Vascular complications were adjudicated by an independent clinical event committee according to VARC-2 criteria. We performed multivariable logistic regression to estimate the effect of baseline and procedural characteristics on any and major vascular complications. Results Between February 2018 and July 2019 500 patients were enrolled undergoing Transcatheter aortic valve replacement (TAVR, N = 496), Balloon aortic valvuloplasty (BAV, N = 2), Mechanical circulatory support (MCS, N = 1) or Endovascular aneurysm repair (EVAR, N = 1). Mean age was 80.8 +/- 6.6 years with a median STS-score of 2.7 [IQR 2.0-4.3] %. MANTA access site complications were major in 20 (4%) and minor in 28 patients (5.6%). Median time to hemostasis was 50 [IQR 20-120] sec. Severe femoral artery calcification, scar presence in groin, longer procedure duration, female gender and history of hypertension were independent predictors for vascular complications. Conclusion In this study, MANTA appeared to be a safe and effective device for large bore access closure under real-world conditions.Peer reviewe