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Aims: To assess the relationship between body mass index (BMI), mortality and mode of death in chronic heart failure (CHF) patients; to define the shape of the relationship between BMI and mortality. Methods and results: We performed a post-hoc analysis of 5010 patients from the Valsartan Heart Failure Trial. The end-points of the study were all-cause and cardiovascular mortality. Mortality rate was 27.2% in underweight patients (BMI b 22 kg/m 2 ), 21.7% in normal weight patients (BMI 22-24.9 kg/m 2 ), 17.9% in overweight patients (BMI 25-29.9 kg/m 2 ) and 16.5% in obese patients (BMI N 30 kg/m 2 ) ( p b 0.0001). The rates of non-cardiovascular death did not differ among groups. The risk of death due to progressive heart failure was 3.4-fold higher in the underweight than in the obese patients ( p b 0.0001). Normal weight, overweight and obese patients had lower risk of death as compared with underweight patients ( p = 0.019, HR 0.76, 95% CI 0.61-0.96; p = 0.0005, HR 0.68, 95% CI 0.55-0.84; p = 0.003, HR 0.67, 95% CI 0.52-0.88, respectively) independently of symptoms, ventricular function, beta-blocker use, C-reactive protein and brain natriuretic peptide levels. Conclusions: In CHF patients a higher BMI is associated with a better prognosis independently of other clinical variables. The relationship between mortality and BMI is monotonically decreasing.

Unspecific peroxygenases (UPOs) enable oxyfunctionalisations of a broad substrate range with unparalleled activities. Tailoring these enzymes for chemo-and regioselective transformations represents a grand challenge due to the difficulties in their heterologous productions. Herein, we performed a protein engineering in S. cerevisiae with the novel MthUPO. Experimental approaches were combined with computational modelling resulting in the screening of more than 5,300 transformants. This protein engineering led to a significant reshaping of the active site as elucidated by molecular dynamics. The k cat /K m was improved by 16.5-fold. Variants were identified with high chemo-and regioselectivities in the oxyfunctionalisation of aromatic and benzylic carbons, respectively. The benzylic hydroxylation was demonstrated to perform with excellent enantioselectivities of 95 % ee. Additionally, the first reported effective exchange of the conserved catalytic Glu residue was observed. File list (2) download file view on ChemRxiv Manuscript_Knorrscheidt et al.pdf (566.94 KiB) download file view on ChemRxiv Supporting_Knorrscheidt et al.pdf (5.26 MiB)

Methods for regioselective N-methylation and -alkylation of unsaturated heterocycles with "off the shelf" reagents are highly sought-after. This reaction could drastically simplify synthesis of privileged bioactive molecules. Here we report engineered and natural methyltransferases for challenging N-(m)ethylation of heterocycles, including benzimidazoles, benzotriazoles, imidazoles and indazoles. The reactions are performed through a cyclic enzyme cascade that consists of two methyltransferases using only iodoalkanes or methyl tosylate as simple reagents. This method enables the selective synthesis of important molecules that are otherwise difficult to access, proceeds with high regioselectivity (r.r. up to > 99 %), yield (up to 99 %), on a preparative scale, and with nearly equimolar concentrations of simple starting materials.

Protein engineering of an unspecific peroxygenase (UPO) was performed with three substrates and six products in parallel by a high throughput GC-MS setup. Modified chemo- and regioselective variants were identified for aliphatic substrates.