Programming Dynamic Division of Labor Using Horizontal Gene Transfer.

The metabolic engineering of microbes has broad applications, including biomanufacturing, bioprocessing, and environmental remediation. The introduction of a complex, multistep pathway often imposes a substantial metabolic burden on the host cell, restraining the accumulation of productive biomass and limiting pathway efficiency. One strategy to alleviate metabolic burden is the division of labor (DOL) in which different subpopulations carry out different parts of the pathway and work together to convert a substrate into a final product. However, the maintenance of different engineered subpopulations is challenging due to competition and convoluted interstrain population dynamics. Through modeling, we show that dynamic division of labor (DDOL), which we define as the DOL between indiscrete populations capable of dynamic and reversible interchange, can overcome these limitations and enable the robust maintenance of burdensome, multistep pathways. We propose that DDOL can be mediated by horizontal gene transfer (HGT) and use plasmid genomics to uncover evidence that DDOL is a strategy utilized by natural microbial communities. Our work suggests that bioengineers can harness HGT to stabilize synthetic metabolic pathways in microbial communities, enabling the development of robust engineered systems for deployment in a variety of contexts.

Microvascular Autoregulation in Skeletal Muscle Using Near-Infrared Spectroscopy and Derivation of Optimal Mean Arterial Pressure in the ICU: Pilot Study and Comparison With Cerebral Near-Infrared Spectroscopy.

IMPORTANCE: Microvascular autoregulation (MA) maintains adequate tissue perfusion over a range of arterial blood pressure (ABP) and is frequently impaired in critical illness. MA has been studied in the brain to derive personalized hemodynamic targets after brain injury. The ability to measure MA in other organs is not known, which may inform individualized management during shock. OBJECTIVES: This study determines the feasibility of measuring MA in skeletal muscle using near-infrared spectroscopy (NIRS) as a marker of tissue perfusion, the derivation of optimal mean arterial pressure (MAPopt), and comparison with indices from the brain. DESIGN: Prospective observational study. SETTING: Medical and surgical ICU in a tertiary academic hospital. PARTICIPANTS: Adult critically ill patients requiring vasoactive support on the first day of ICU admission. MAIN OUTCOMES AND MEASURES: Fifteen critically ill patients were enrolled. NIRS was applied simultaneously to skeletal muscle (brachioradialis) and brain (frontal cortex) while ABP was measured continuously via invasive catheter. MA correlation indices were calculated between ABP and NIRS from skeletal muscle total hemoglobin (MVx), muscle tissue saturation index (MOx), brain total hemoglobin (THx), and brain tissue saturation index (COx). Curve fitting algorithms derive the MAP with the lowest correlation index value, which is the MAPopt. RESULTS: MAPopt values were successfully calculated for each correlation index for all patients and were frequently (77%) above 65 mm Hg. For all correlation indices, median time was substantially above impaired MA threshold (24.5-34.9%) and below target MAPopt (9.0-78.6%). Muscle and brain MAPopt show moderate correlation (MVx-THx r = 0.76, p < 0.001; MOx-COx r = 0.69, p = 0.005), with a median difference of -1.27 mm Hg (-9.85 to -0.18 mm Hg) and 0.05 mm Hg (-7.05 to 2.68 mm Hg). CONCLUSIONS AND RELEVANCE: This study demonstrates, for the first time, the feasibility of calculating MA indices and MAPopt in skeletal muscle using NIRS. Future studies should explore the association between impaired skeletal muscle MA, ICU outcomes, and organ-specific differences in MA and MAPopt thresholds.

Programming dynamic division of labor using horizontal gene transfer.

The metabolic engineering of microbes has broad applications, including in biomanufacturing, bioprocessing, and environmental remediation. The introduction of a complex, multi-step pathway often imposes a substantial metabolic burden on the host cell, restraining the accumulation of productive biomass and limiting pathway efficiency. One strategy to alleviate metabolic burden is division of labor (DOL), in which different subpopulations carry out different parts of the pathway and work together to convert a substrate into a final product. However, the maintenance of different engineered subpopulations is challenging due to competition and convoluted inter-strain population dynamics. Through modeling, we show that dynamic division of labor (DDOL) mediated by horizontal gene transfer (HGT) can overcome these limitations and enable the robust maintenance of burdensome, multi-step pathways. We also use plasmid genomics to uncover evidence that DDOL is a strategy utilized by natural microbial communities. Our work suggests that bioengineers can harness HGT to stabilize synthetic metabolic pathways in microbial communities, enabling the development of robust engineered systems for deployment in a variety of contexts.

Twelve Tips to implement Curriculum Changes in times of Economic Austerity.

This article was migrated. The article was marked as recommended. Curriculum change is a recurring challenge facing most educational teams. Economic austerity has an impact on these processes in that clinical workloads increase and additional funds to drive curriculum change are lacking. We faced significant challenges having to implement substantial changes to the Year 3 and 4 undergraduate curricula in a large teaching hospital in the United Kingdom. The changes are now implemented successfully and we have taken the opportunity to identify factors that allowed us to drive change and achieve our aims. Much has been written about curriculum change as an academic challenge but comparatively little is known about how to drive such change on the ground and strategies to drive curriculum change during times of ongoing financial austerity are lacking. Here, we reflect on our experience and provide tips for educational teams on how to turn change into an opportunity, despite economic austerity and ever-increasing clinical workload.