Tricarbonyliron(0) complexes of bio-derived η4 cyclohexadiene ligands: An approach to analogues of oseltamivir

We have prepared novel [η4] and [η5]+ tricarbonyliron complexes from an unusual enantiopure cyclohexadiene ligand that possesses a quaternary stereocentre; this in turn is prepared through biotransformation of an aromatic ring. The cyclohexadiene ligand initially possessed two hydroxyl groups, both of which could be substituted with other functionality by means of an overall [η4] → [η5]+ → [η4] → [η5]+ → [η4] sequence. From six novel tricarbonyliron complexes which have been prepared, three have been characterised by x-ray crystallography. The reaction sequence we describe is potentially of relevance to the synthesis of analogues of the anti-influenza drug oseltamivir. In addition, the failure of an attempted addition of a bulky nitrogen nucleophile to an [η5]+ complex sheds light on the limits of reactivity for such additions. Thus, two bulky nucleophiles which are each known to add successfully to unencumbered [η5]+ complexes seemingly cannot be added sequentially to adjacent positions on the cyclohexadiene ligand

Zoeken naar een indicator voor mobiel N in de bodem

De nitraatconcentraties in het grondwater zijn op veel plaatsen in Nederland te hoog. Verandering in bemestingsbeleid zullen naar verwachting effect hebben op nitraatuitspoeling naar grondwater en oppervlaktewater. Monitoren van nitraatconcentraties in het grondwater is echter zeer arbeidsintensief. Daarom is gezocht naar een bodemparameter, die reageert op veranderingen in bemesting en daarom als indicator voor verandering in nitraatuitspoeling kan dienen. Bodemmonsters zijn genomen in langjarige bemestingsproeven en diverse bodemparameters zijn gemeten en vergeleken. Geen van de parameters gaf een duidelijke reactie op bemesting. De nitraatconcentratie in het grondwater reageerde wel. Dit lijkt de beste indicator voor uitspoeling te zijn

Ontwikkeling van een indicator om te sturen op nitraat; toetsing van de regressiemodellen voor nitraat

Binnen het project ¿Sturen op Nitraat¿ zijn regressiemodellen ontwikkeld. In dit rapport wordt op verschillende manieren getoetst hoe nauwkeurig de nitraatconcentratie uit waarnemingen aan de indicatoren kan worden voorspeld met behulp van de regressiemodellen. Dit wordt gedaan op basis van de metingen van het vierde meetseizoen. Het blijkt dat nieuwe meetpunten veelal binnen de 95-%-betrouwbaarheidsintervallen van de voorspelling vallen, wanneer deze is gebaseerd op de meest eenvoudige modellen en de gemeten Nminnitraat. Dit eenvoudige model, met bodem-Gt-gewas-combinatie (cluster) en Nminnitraat is bovendien het meest stabiele en praktisch toepasbare mode

Ontwikkeling van een indicator om te sturen op nitraat; gegevens en regressieanalyse op basis van drie meetseizoenen (2000-2001, 2001-2002 en 2002-2003)

In het project `Sturen op Nitraat¿ wordt gezocht naar indicatoren waarmee de nitraatconcentratie in het grondwater kan worden voorspeld. Uit een analyse van de meetresultaten van drie meetseizoenen (2000/2001, 2001/2002 en 2002/2003) blijkt dat de nitraatconcentratie het best kan worden voorspeld uit het nitraatgedeelte van de hoeveelheid Nmineraal die zich in het najaar in de bovenste 90 cm van de bodem bevindt, en een clusterindeling die is gebaseerd op een combinatie van bodemsoort, grondwatertrap en gewas. Het verdient aanbeveling te onderzoeken of het nitraatdeel van Nmineraal bruikbaar is voor sturing op bedrijfsniveau (beïnvloedbaarheid), of voor monitoring van effecten van maatregelen (doelgerichtheid en meetbaarheid)

The complexity of screening PMS2 in DNA isolated from formalin-fixed paraffin-embedded material

Germline variants in the DNA mismatch repair (MMR) gene PMS2 cause 1-14% of all Lynch Syndrome cancers. Correct variant analysis of PMS2 is complex due to the presence of multiple pseudogenes and the occurrence of gene conversion. The analysis complexity increases in highly fragmented DNA from formalin-fixed paraffin-embedded (FFPE) tissue. Here we describe a reliable approach to detect true PMS2 variants in fragmented DNA. A custom NGS panel designed for FFPE tissue was used targeting four MMR genes, POLE and POLD1. Amplicon design for PMS2 was based on the position of paralogous sequence variants (PSVs) that distinguish PMS2 from its pseudogenes. PMS2 variants in exons 1-11 can be correctly curated based on this information. For exons 12-15 this is less reliable as these undergo gene conversion. Using this method, we screened PMS2 variants in 125 MMR-deficient tumors. Of the 125 tumors tested, six were unexplained MMR-deficient tumors with solitary PMS2 protein expression loss. In these six tumors two unclassified variants (class 3) and five variants likely affecting function (class 4/5) were detected in PMS2. One microsatellite unstable tumor with positive staining for all MMR proteins was found to carry a frameshift PMS2 variant (class 5). No class 4 or class 5 PMS2 variants were detected in tumors with other patterns of MMR protein expression loss.Molecular tumour pathology - and tumour geneticsMTG2 - Moleculaire genetica van gastrointestinale tumore

Declining detection rates for APC and biallelic MUTYH variants in polyposis patients, implications for DNA testing policy

This study aimed to determine the prevalence of APC-associated familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) in a large cohort, taking into account factors as adenoma count and year of diagnosis. All application forms used to send patients in for APC and MUTYH variant analysis between 1992 and 2017 were collected (n = 2082). Using the data provided on the application form, the APC and biallelic MUTYH prevalence was determined and possible predictive factors were examined using multivariate multinomial logistic regression analysis in SPSS. The prevalence of disease causing variants in the APC gene significantly increases with adenoma count while MAP shows a peak prevalence in individuals with 50–99 adenomas. Logistic regression analysis shows significant odds ratios for adenoma count, age at diagnosis, and, interestingly, a decline in the chance of finding a variant in either gene over time. Moreover, in 22% (43/200) of patients with FAP-related extracolonic manifestations a variant was identified. The overall detection rates are above 10% for patients with >10 adenomas aged 20 adenomas aged T variant in the tumor or a first-degree relative with >10 adenomas. Therefore, APC and MUTYH testing in patients with >10 adenomas aged 20 adenomas aged <70 is advised. Almost all FAP and MAP patients not meeting these criteria showed other characteristics that can be used as an indication to prompt genetic testing

Serum methylarginines and spirometry-measured lung function in older adults

Rationale: Methylarginines are endogenous nitric oxide synthase inhibitors that have been implicated in animal models of lung disease but have not previously been examined for their association with spirometric measures of lung function in humans. Objectives: This study measured serum concentrations of asymmetric and symmetric dimethylarginine in a representative sample of older community-dwelling adults and determined their association with spirometric lung function measures. Methods: Data on clinical, lifestyle, and demographic characteristics, methylated arginines, and L-arginine (measured using LC-MS/MS) were collected from a population-based sample of older Australian adults from the Hunter Community Study. The five key lung function measures included as outcomes were Forced Expiratory Volume in 1 second, Forced Vital Capacity, Forced Expiratory Volume in 1 second to Forced Vital Capacity ratio, Percent Predicted Forced Expiratory Volume in 1 second, and Percent Predicted Forced Vital Capacity. Measurements and Main Results: In adjusted analyses there were statistically significant independent associations between a) higher asymmetric dimethylarginine, lower Forced Expiratory Volume in 1 second and lower Forced Vital Capacity; and b) lower L-arginine/asymmetric dimethylarginine ratio, lower Forced Expiratory Volume in 1 second, lower Percent Predicted Forced Expiratory Volume in 1 second and lower Percent Predicted Forced Vital Capacity. By contrast, no significant associations were observed between symmetric dimethylarginine and lung function. Conclusions: After adjusting for clinical, demographic, biochemical, and pharmacological confounders, higher serum asymmetric dimethylarginine was independently associated with a reduction in key measures of lung function. Further research is needed to determine if methylarginines predict the decline in lung function

Temporal dynamics of sitting behavior at work

Sitting for prolonged periods of time impairs people’s health. Prior research has mainly investigated sitting behaviour on an aggregate level, e.g., by analysing total sitting time per day. By contrast, taking a dynamic approach, here we conceptualise sitting behaviour as a continuous chain of sit-to-stand and stand-to-sit transitions. We use multilevel time-to-event analysis to analyse the timing of these transitions. We analyse ~30,000 objectively-measured posture transitions from 156 people during worktime. Results indicate that the temporal dynamics of sit-to-stand transitions differ from stand-to-sit transitions, that people are quicker to switch postures later on the workday, and quicker to stand up after having been more active in the recent hours. We found no evidence for associations with physical fitness. Altogether, these findings provide insights into the origins of people’s stand-up and sit-down decisions, show that sitting behaviour is fundamentally different from exercise behaviour, and provide pointers for the development of interventions