Accelerated Polypeptide Synthesis via N-Carboxyanhydride Ring Opening Polymerization in Continuous Flow.

In nature, polypeptide-based materials are ubiquitous, yet their synthetic production is hampered by high cost, limited scalability, and often stringent reaction conditions. Herein an elegant approach is presented for N-carboxyanhydride ring opening polymerization (NCA ROP) of Nε-benzyloxycarbonyl-l-lysine (ZLL) and γ-benzyl-l-glutamate (BLG) NCA in continuous flow. The polymerization is initiated by primary amine initiators using N,N-dimethylformamide (DMF) as solvent. Carrying out the reaction in a silicon microflow reactor speeds up the rate of ROP (92% conversion in 40 min in flow as opposed to 6 h in batch) due to highly efficient permeation of CO2 through the reactor tubing. The polymerization strategy provides a facile, scale-up friendly alternative to traditional batch mode polymerization and has the capability of streamlining NCA ROP.

Precise Polymer Synthesis by Autonomous Self-Optimizing Flow Reactors.

A novel continuous flow system for automated high-throughput screening, autonomous optimization, and enhanced process control of polymerizations was developed. The computer-controlled platform comprises a flow reactor coupled to size exclusion chromatography (SEC). Molecular weight distributions are measured online and used by a machine-learning algorithm to self-optimize reactions towards a programmed molecular weight by dynamically varying reaction parameters (i.e. residence time, monomer concentration, and control agent/initiator concentration). The autonomous platform allows targeting of molecular weights in a reproducible manner with unprecedented accuracy (<2.5 % deviation from pre-selected goal) for both thermal and light-induced reactions. For the first time, polymers with predefined molecular weights can be custom made under optimal reaction conditions in an automated, high-throughput flow synthesis approach with outstanding reproducibility.

Heart rate reduction and exercise performance in recent onset heart failure with reduced ejection fraction: arguments for beta-blocker hypo-response.

OBJECTIVE: Beta blockers reduce all-cause mortality and readmissions in heart failure with reduced ejection fraction (HFrEF), which may be explained by their effect on heart rate (HR). This study assessed the impact of HR reduction with beta blockers on exercise capacity in recent onset HFrEF. METHODS AND RESULTS: Fifty consecutive patients with recent onset HFrEF (<30 days) performed a standardized exercise protocol with respiratory gas analysis at baseline as well as after 6 and 12 months. Patients participated in a quality of care programme aiming to achieve guideline-recommended target doses for beta-blocker therapy. At baseline, 6 and 12 months, 36%, 70% and 62% of patients, respectively, had a resting HR<70 bpm. Beta-blocker dose after 12 months was comparable in patients with resting HR<70 versus ≥70 bpm (P value=0.631). However, with similar dose uptitration, the former versus the latter had a significantly larger HR reduction (17±22 versus 4±15 bpm; P value=0.027). Peak oxygen consumption (VO2max) was significantly higher when resting HR was <70 versus ≥70 bpm (17.5±5.5 versus 14.4±3.3 mL/min/kg, respectively; P value=0.038). Similar results were observed after 6 months. Patients in whom resting HR decreased at follow-up compared to baseline had a 2.0±3.2 mL/min/kg increase in VO2max compared to a 1.2±7.7 mL/min/kg increase in patients who did not demonstrate a lower resting HR (P value=0.033). CONCLUSIONS: In recent onset HFrEF, exercise performance was better when resting HR was controlled <70 bpm with beta-blocker therapy. However, despite aggressive dose uptitration, many patients did not achieve this target as they had little HR reduction with beta-blocker therapy.