84 research outputs found
Reactivity and selectivity in glycosylation reactions
The glycosylation reaction is a pivotal reaction in
creating new and complex oligosaccharides. These biologically relevant
compounds must be obtained in enough quantity and in pure, well-defined form.
Organic synthesis can provide these compounds, but efficient methods
regarding their selective synthesis are often absent. Every saccharide
building block is coupled to another in a glycosylation reaction, which must
be both regioselective and stereoselective. For the stereoselectivity of this
reaction common protocols are not generally applicable. This thesis
investigates the stereoselectivity of the glycosylation reaction from the
standpoint of the sugar acceptor, rather than from the sugar donor which has
been the focal point for many decades. The results obtained showed that a
scale of selectivities can be obtained by changing the reactivity of the
acceptor. The trends within the acceptor reactivity are valid for all donors
studied, but some donors are more susceptible than others to changes in
acceptor reactivity. In the second part of this thesis the spatial identity
of intermediates in the glycosylation reaction are investigated. Experimental
and computational techniques combined resulted in an effective model to
understand the glycosylation reaction on the SN1-side of the reaction
spectrum when different functional groups are located on the carbohydrate
donor.
Bio-organic Synthesi
Strafeisverhoging bij geweld tegen kwalificerende slachtoffers:Op naar een gekwalificeerd delict voor kwalificerende slachtoffers?
Mapping the Relationship between Glycosyl Acceptor Reactivity and Glycosylation Stereoselectivity
Bio-organic Synthesi
Synthesis of O-1-O-6 Substituted Positional Isomers of D-Glucose-Thioether Ligands and Their Ruthenium Polypyridyl Conjugates
Metals in Catalysis, Biomimetics & Inorganic Material
Low antithrombin levels are associated with low risk of cardiovascular death but are a risk factor for cancer mortality
Background: Thrombosis is common in subjects suffering from cardiovascular diseases (CVD) and cancer. Hypercoagulation plays a pivotal role in the pathophysiology of thrombosis. Therefore, the inactivation of thrombin, the key enzyme in coagulation, is tightly regulated via antithrombin (AT). AT deficiency is related to thrombosis and cardiovascular death. In this study we investigated the association between AT levels and mortality, in particularly cardiovascular- related and cancer-related death in the general population. Methods: We studied the association of AT levels and mortality in a prospective cohort sampled from the general Italian population (n = 19,676). AT levels were measured in the baseline samples, and mortality was recorded during a median follow-up period of 8.2 years. Cox regression was performed to investigate the association of all-cause, CVD-related and cancerrelated mortality with variations in AT levels. Results: In total, 989 subjects died during follow-up, of which 373 subjects of CVD and 353 of cancerrelated causes. Cox analysis revealed that, after adjustment for age, sex, current smoking, BMI, diabetes, hypertension, hypercholesterolemia, history of cardiovascular disease, history of cancer, vitamin K antagonists, antiplatelet medication, heparin and oral contraceptives AT levels were not associated with all-cause mortality (HRQ1vsQ5: 0.92, 95% CI:0.74- 1.15). Interestingly, the risk of CVD-related mortality was reduced in subjects with low AT levels compared to subjects with higher AT levels, after adjustment for age and sex and other confounders did not change the association (HRQ1vsQ5: 0.64, 95% CI:0.44-0.91). Moreover, low AT levels were associated with increased cancer mortality in a fully adjusted model (HRQ1vsQ2-5: 1.26, 95% CI:0.88-1.81). Conclusions: Low AT levels are associated to a lower risk of fatal cardiovascular events in the general population, regardless of age, sex and medication use. In contrast, low AT levels are associated with lower cancer survival. For the first time we show that AT levels lower than the normal range in the general population, even before the development or diagnosis of cancer, are associated with an elevated risk of cancer death
Dynamic Interactive Social Cognition Training in Virtual Reality (DiSCoVR) versus Virtual Reality Relaxation (VRelax) for People With a Psychotic Disorder:A Single-Blind Multicenter Randomized Controlled Trial
BACKGROUND AND HYPOTHESIS: Social cognition training (SCT), an intervention for social cognition and social functioning, might be improved by using virtual reality (VR), because VR may offer better opportunities to practice in a potentially more realistic environment. To date, no controlled studies have investigated VR-SCT. This study investigated a VR-SCT, "DiSCoVR". We hypothesized that DiSCoVR would improve social cognition and social functioning. STUDY DESIGN: Participants were randomized to DiSCoVR (n = 41) or VR relaxation ('VRelax', n = 40), an active control condition, and completed 16 twice-weekly sessions. Three assessments (baseline, posttreatment, and 3-month follow-up) were performed by blinded assessors. The primary outcome was social cognition (emotion perception and theory of mind). Secondary outcomes included social functioning (measured with an interview and experience sampling), psychiatric symptoms, information processing, and self-esteem. Data were analyzed using mixed-models regression analysis. Treatment effects were evaluated by the time by condition interaction terms. STUDY RESULTS: No significant time by condition interactions were found for any of the outcome variables, indicating an absence of treatment effects. Between-group effect sizes ranged from negligible to moderate (Cohen's d < |0.53|). Main effects of time were found for several outcomes. CONCLUSIONS: These results suggest that DiSCoVR was not effective, possibly because of inadequate simulation of emotional expressions in VR. This lack of efficacy may indicate that current SCT protocols are relatively unsuitable for improving social functioning. Previous studies showed small to moderate effects on higher order social cognition, but the SCT approach may need critical reevaluation, as it may not sufficiently lead to functional improvement
Characterization of glycosyl dioxolenium ions and their role in glycosylation reactions
Controlling the chemical glycosylation reaction remains the major challenge in the synthesis of oligosaccharides. Though 1,2-trans glycosidic linkages can be installed using neighboring group participation, the construction of 1,2-cis linkages is difficult and has no general solution. Long-range participation (LRP) by distal acyl groups may steer the stereoselectivity, but contradictory results have been reported on the role and strength of this stereoelectronic effect. It has been exceedingly difficult to study the bridging dioxolenium ion intermediates because of their high reactivity and fleeting nature. Here we report an integrated approach, using infrared ion spectroscopy, DFT computations, and a systematic series of glycosylation reactions to probe these ions in detail. Our study reveals how distal acyl groups can play a decisive role in shaping the stereochemical outcome of a glycosylation reaction, and opens new avenues to exploit these species in the assembly of oligosaccharides and glycoconjugates to fuel biological research.Bio-organic Synthesi
Molecular characterization of MRSA collected during national surveillance between 2008 and 2019 in the Netherlands
Background.Although the Netherlands is a country with a low endemic level, methicillin-resistant Staphylococcus aureus (MRSA) poses a significant health care problem. Therefore, high coverage national MRSA surveillance has been in place since 1989. To monitor possible changes in the type-distribution and emergence of resistance and virulence, MRSA isolates are molecularly characterized.Methods.All 43,321 isolates from 36,520 persons, collected 2008-2019, were typed by multiple-locus variable number tandem repeats analysis (MLVA) with simultaneous PCR detection of the mecA, mecC and lukF-PV genes, indicative for PVL. Next-generation sequencing data of 4991 isolates from 4798 persons were used for whole genome multi-locus sequence typing (wgMLST) and identification of resistance and virulence genes.Results.We show temporal change in the molecular characteristics of the MRSA population with the proportion of PVL-positive isolates increasing from 15% in 2008-2010 to 25% in 2017-2019. In livestock-associated MRSA obtained from humans, PVL-positivity increases to 6% in 2017-2019 with isolates predominantly from regions with few pig farms. wgMLST reveals the presence of 35 genogroups with distinct resistance, virulence gene profiles and specimen origin. Typing shows prolonged persistent MRSA carriage with a mean carriage period of 407 days. There is a clear spatial and a weak temporal relationship between isolates that clustered in wgMLST, indicative for regional spread of MRSA strains.Conclusions.Using molecular characterization, this exceptionally large study shows genomic changes in the MRSA population at the national level. It reveals waxing and waning of types and genogroups and an increasing proportion of PVL-positive MRSA.A group of bacteria that cause difficult-to-treat infections in humans is methicillin-resistant Staphylococcus aureus (MRSA). The aim of this study was to monitor changes in the spread of MRSA, their disease causing potential and resistance to antibiotics used to treat MRSA infections. MRSA from patients and their contacts in the Netherlands were collected over a period of 12 years and characterized. This revealed new types of MRSA emerged and others disappeared. An increasing number of MRSA produces a protein called PVL toxin, enabling MRSA to cause more severe infections. Also, some people appear to carry MRSA without any disease for more than a year. These findings suggest an increasing disease potential of MRSA and possible unnoticed sources of infection. Consequently, it is important to maintain monitoring of these infections to minimize MRSA spread.Schouls et al. characterize 43,321 methicillin-resistant Staphylococcus aureus (MRSA) isolates obtained between 2008 and 2019 in the Netherlands. Genomic changes occur in the MRSA population, with increases in the proportion of PVL-positive MRSA.Molecular basis of bacterial pathogenesis, virulence factors and antibiotic resistanc
Ageism and Dementia
This chapter explores the relationship between ageism and dementia. Although dementia is not an unavoidable consequence of ageing, increasing age is the biggest risk factor for having this disease. The prevalence of dementia increases exponentially with age and 95% of those with Alzheimer's Disease, the most common form of dementia, are aged 65 or over. Dementia often has strong negative connotations, partly driven by alarmist media portrayals of the disease, which means that people living with the condition can experience the `double stigma' of ageism and dementia-related discrimination. The stigma attached to dementia can have significant implications for quality of life through, for example, decreased social engagement, reduced self-esteem, increased carer burden and sub-standard healthcare, a situation that is exacerbated by low levels of diagnosis and inadequate training of medical professionals. Despite attempts by governments and not for profit organisations to tackle dementia-related stigma, there remains a strong need to raise awareness of the realities of living with dementia and to reduce the impact of discrimination. This chapter explores the inter-connections and overlaps between ageing and discrimination because someone has dementia. The relationship between dementia and age is discussed, followed by an exploration of the impacts of dementia-related stigma for the individual and society. The chapter continues by analysing the role of the media in fuelling stigma and how having dementia can impact on the receipt of health and social care services. The chapter explores the implications of dementia stigma for social engagement and ends by considering how perceptions of dementia are reflected in research funding
- …