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Sterols are among the most abundant lipids in eukaryotic cells yet are synthesized through notoriously long metabolic pathways. It has been proposed that the molecular evolution of such pathways must have required each step to increase the capacity of its product to condense and order phospholipids. Here, we carry out a systematic analysis of the ergosterol pathway that leverages the yeast vacuole’s capacity to phase separate into ordered membrane domains. In the post-synthetic steps specific to ergosterol biosynthesis, we find that successive modifications act to oscillate ordering capacity, settling on a level that supports phase separation while retaining fluidity of the resulting domains. Simulations carried out with each intermediate showed how conformers in the sterol’s alkyl tail are capable of modulating long-range ordering of phospholipids, which could underlie changes in phase behavior. Our results indicate that the complexity of sterol metabolism could have resulted from the need to balance lipid interactions required for membrane organization. 

We report a power-efficient analog front-end integrated circuit (IC) for multi-channel, dual-band subcortical recordings. In order to achieve high-resolution multi-channel recordings with low power consumption, we implemented an incremental ΔΣ ADC (IADC) with a dynamic zoom-and-track scheme. This scheme continuously tracks local field potential (LFP) and adaptively adjusts the input dynamic range (DR) into a zoomed sub-LFP range to resolve tiny action potentials. Thanks to the reduced DR, the oversampling rate of the IADC can be reduced by 64.3% compared to the conventional approach, leading to significant power reduction. In addition, dual-band recording can be easily attained because the scheme continuously tracks LFPs without additional on-chip hardware. A prototype four-channel front-end IC has been fabricated in 180 nm standard CMOS processes. The IADC achieved 11.3-bit ENOB at 6.8 μW, resulting in the best Walden and SNDR FoMs, 107.9 fJ/c-s and 162.1 dB, respectively, among two different comparison groups: the IADCs reported up to date in the state-of-the-art neural recording front-ends; and the recent brain recording ADCs using similar zooming or tracking techniques to this work. The intrinsic dual-band recording feature reduces the post-processing FPGA resources for subcortical signal band separation by >45.8%. The front-end IC with the zoom-and-track IADC showed an NEF of 5.9 with input-referred noise of 8.2 μVrms, sufficient for subcortical recording. The performance of the whole front-end IC was successfully validated through in vivo animal experiments. 

Substrates engineered to undergo a 1,4-C–H insertion to yield benzocyclobutenes resulted in a novel elimination reaction to yieldortho-quinone dimethide (o-QDM) products that undergo Diels–Alder or hetero-Diels–Alder cycloadditions. 

Abstract TEM-1 β-lactamase degrades β-lactam antibiotics with a strong preference for penicillins. Sequence reconstruction studies indicate that it evolved from ancestral enzymes that degraded a variety of β-lactam antibiotics with moderate efficiency. This generalist to specialist conversion involved more than 100 mutational changes, but conserved fold and catalytic residues, suggesting a role for dynamics in enzyme evolution. Here, we develop a conformational dynamics computational approach to rationally mold a protein flexibility profile on the basis of a hinge-shift mechanism. By deliberately weighting and altering the conformational dynamics of a putative Precambrian β-lactamase, we engineer enzyme specificity that mimics the modern TEM-1 β-lactamase with only 21 amino acid replacements. Our conformational dynamics design thus re-enacts the evolutionary process and provides a rational allosteric approach for manipulating function while conserving the enzyme active site.