Efficient bio-butanol production from lignocellulosic waste by elucidating the mechanisms of Clostridium acetobutylicum response to phenolic inhibitors.

Lignocellulosic biomass is considered abundant renewable feedstock to constitute a green and environmentally friendly approach for biofuels (bio-butanol) production as an effective substitute for fossil resources. However, a variety of fermentable inhibitors can be generated in hydrolysates during the biomass pretreatment process. Among them, phenolics including phenolic acids and phenolic aldehydes are the most toxic inhibitors to solventogenic clostridia for bio-butanol production. This study elucidates the physiological mechanism of Clostridium acetobutylicum ATCC 824 response to phenolic inhibitors by the integration of kinetics and transcriptional analysis. Butanol fermentations were stressed by 0.4 g/L phenolic acids or 0.4 g/L phenolic aldehydes at 12 h at the beginning of solventogenesis. With post-stress for 12 h, butanol titer was 7.01 g/L in fermentation with phenolic acid stress, while only 5.82 g/L butanol was produced in the case of phenolic aldehydes stress. Reductions in the two fermentations were 27.6% and 40.0% in comparison with the control (without stress), indicated that phenolic aldehydes had a stronger inhibitory effect on solvents synthesis in C. acetobutylicum than phenolic acids. Additionally, the transcriptional analysis revealed that phenolics altered the gene expression profiles related to membrane transporters such as ATP-binding cassette (ABC)-transporter and phosphotransferase system (PTS), glycolysis, and heat shock proteins. The lower expression levels of PTS-related genes might result in reduced glucose consumption and finally inhibited solvents synthesis under phenolic aldehydes stress. Some genes encoding histidine kinase (CA_C0323, CA_C0903, and CA_C3319) were also affected by phenolics, which might inhibit sporulation. In conclusion, our results provide valuable guidance for the construction of robust strain to efficiently produce bio-butanol from lignocellulosic biomass.

Co-production of solvents and organic acids in butanol fermentation by Clostridium acetobutylicum in the presence of lignin-derived phenolics.

Co-production of solvents (butanol, acetone, and ethanol) and organic acids (butyrate and acetate) by Clostridium acetobutylicum using lignocellulosic biomass as a substrate could further enlarge the application scope of butanol fermentation. This is mainly because solvents and organic acids could be used for production of fine chemicals such as butyl butyrate, butyl oleate, etc. However, many phenolic fermentation inhibitors are formed during the pretreatment process because of lignin degradation. The present study investigated the effects of five typical lignin-derived phenolics on the biosynthesis of solvents and organic acids in C. acetobutylicum ATCC 824. Results obtained in 100 mL anaerobic bottles indicated that butanol concentration was enhanced from 10.29 g L-1 to 11.36 g L-1 by the addition of 0.1 g L-1 vanillin. Subsequently, a pH-control strategy was proposed in a 5 L anaerobic fermenter to alleviate the "acid crash" phenomenon and improve butanol fermentation performance, simultaneously. Notably, organic acid concentration was enhanced from 6.38 g L-1 (control) to a high level of 9.21-12.57 g L-1 with vanillin or/and vanillic acid addition (0.2 g L-1) under the pH-control strategy. Furthermore, the butyrate/butanol ratio reached the highest level of 0.80 g g-1 with vanillin/vanillic acid co-addition, and solvent concentration reached 13.85 g L-1, a comparable level to the control (13.69 g L-1). The effectiveness and robustness of the strategy for solvent and organic acid co-production was also verified under five typical phenolic environments. In conclusion, these results suggest that the proposed process strategy would potentially promote butanol fermentative products from renewable biomass.

Obesity and Pediatric Drug Development.

There is a lack of dosing guidelines for use in obese children. Moreover, the impact of obesity on drug safety and clinical outcomes is poorly defined. The paucity of information needed for the safe and effective use of drugs in obese patients remains a problem, even after drug approval. To assess the current incorporation of obesity as a covariate in pediatric drug development, the pediatric medical and clinical pharmacology reviews under the Food and Drug Administration (FDA) Amendments Act of 2007 and the FDA Safety and Innovation Act (FDASIA) of 2012 were reviewed for obesity studies. FDA labels were also reviewed for statements addressing obesity in pediatric patients. Forty-five drugs studied in pediatric patients under the FDA Amendments Act were found to have statements and key words in the medical and clinical pharmacology reviews and labels related to obesity. Forty-four products were identified similarly with pediatric studies under FDASIA. Of the 89 product labels identified, none provided dosing information related to obesity. The effect of body mass index on drug pharmacokinetics was mentioned in only 4 labels. We conclude that there is little information presently available to provide guidance related to dosing in obese pediatric patients. Moving forward, regulators, clinicians, and the pharmaceutical industry should consider situations in drug development in which the inclusion of obese patients in pediatric trials is necessary to facilitate the safe and effective use of new drug products in the obese pediatric population.

Neonatal Safety Information Reported to the FDA During Drug Development Studies.

BACKGROUND: Relatively few neonatal drug development studies have been conducted, but an increase is expected with the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA). Understanding the safety of drugs studied in neonates is complicated by the unique nature of the population and the level of illness. The objective of this study was to examine neonatal safety data submitted to the FDA in studies pursuant to the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) between 1998 and 2015. METHODS: FDA databases were searched for BPCA and/or PREA studies that enrolled neonates. Studies that enrolled a minimum of 3 neonates were analyzed for the presence and content of neonatal safety data. RESULTS: The analysis identified 40 drugs that were studied in 3 or more neonates. Of the 40 drugs, 36 drugs received a pediatric labeling change as a result of studies between 1998 and 2015, that included information from studies including neonates. Fourteen drugs were approved for use in neonates. Clinical trials for 20 of the drugs reported serious adverse events (SAEs) in neonates. The SAEs primarily involved cardiovascular events such as bradycardia and/or hypotension or laboratory abnormalities such as anemia, neutropenia, and electrolyte disturbances. Deaths were reported during studies of 9 drugs. CONCLUSIONS: Our analysis revealed that SAEs were reported in studies involving 20 of the 40 drugs evaluated in neonates, with deaths identified in 9 of those studies. Patients enrolled in studies were often critically ill, which complicated determination of whether an adverse event was drug-related. We conclude that the traditional means for collecting safety information in drug development trials needs to be adjusted for neonates and will require the collaboration of regulators, industry, and the clinical and research communities to establish appropriate definitions and reporting strategies for the neonatal population.