Technology Development Initiative Paper of the Month

Complete biosynthesis of cannabinoids and their unnatural analogues in yeast. Nature

The study and medicinal use of cannabinoids has been hampered by the legal scheduling of Cannabis, the low in planta abundances of nearly all of the dozens of known cannabinoids, and their structural complexity, which limits bulk chemical synthesis. Here we report the complete biosynthesis of the major cannabinoids cannabigerolic acid, Δ9-tetrahydrocannabinolic acid, cannabidiolic acid, Δ9-tetrahydrocannabivarinic acid and cannabidivarinic acid in Saccharomyces cerevisiae, from the simple sugar galactose. Furthermore, we established a biosynthetic approach that harnessed the promiscuity of several pathway genes to produce cannabinoid analogues. Feeding different fatty acids to our engineered strains yielded cannabinoid analogues with modifications in the part of the molecule that is known to alter receptor binding affinity and potency [Read More]

The acceptability of overdose alert and response technologies: introducing the TPOM-ODART framework. Harm Reduct J

A TPOM-ODART framework, a model of overdose alert and response technologies (ODART) based on the existing health information technology TPOM dataset, was developed to better understand factors involved in harm reduction technology acceptability to people who use opioids (PWUO). Concerns of trust, readiness, accessibility, and capacity were found to be key factors in engaging and retaining PWUO in ODRAT interventions. [Read More]

Sensitive multicolor indicators for monitoring norepinephrine in vivo. Nat Methods.

Existing GPCR-based Norepinephrine sensors are based on alpha-2a adrenergic receptors and do not exhibit the kinetic properties needed to investigate in vivo NE dynamics in response to different drugs. Kagiampaki et al. developed a new set of fluorescent indicators based on the alpha-1a adrenergic receptors. The nLight sensors combined with fiber photometry and two-photon imaging could be used to investigate spatial and temporal aspects of Norepinephrine signaling in animal models of substance use disorder. [Read More]

Highly accurate protein structure prediction for the human proteome Nature.

Determining complete protein structures is difficult as sufficient quantities need to be purified; protein size, transmembrane domains, and susceptibility to conformational changes create inconsistencies; and the work can take months to years. Tunyasuvunakool et al. applied AlphaFold to predict full-length structures with detailed chemical components of nearly the entire human proteome (98.5%) as well as ~20 other organisms and provided this data in a public database. Since publication, the authors updated AlphaFold (version 2) shortening days-long prediction computation to minutes/hours and the database now has over 200 million protein structures. [Read More]

Engineering of NEMO as calcium indicators with large dynamics and high sensitivity. Nat Methods.

Current genetically encoded calcium indicators have suboptimal dynamic range and peak signal-to-baseline ratios. Li et al. engineered a new series of mNG-based calcium indicators (NEMO) that exhibit fast kinetics with up to 100-fold increase in dynamic range and 20-fold increase in signal-to-baseline ratios when NEMO sensors were compared to GCaMP6m or NCaMP7. Increased fluorescence and dynamic range of NEMO should facilitate the in vivo monitoring of calcium changes in deep brain structures and cellular organelles. [Read More]

Revealing the structure of pharmacobehavioral space through motion sequencing. Nat Neurosci.

Standard behavioral assays that are used for screening candidate therapeutic drugs, such as the elevated plus maze and forced swim test, yield only one or two dimensions of information. Wiltschko et al. used a machine learning algorithm called MoSeq (for motion sequencing) to analyze 3D video recordings of twenty minutes of open field mouse activity, thereby obtaining a much higher dimensional readout of behavior in response to a wide variety of psychoactive drugs and doses. [Read More]

The Successor Representation: Its Computational Logic and Neural Substrates. J Neurosci.

In this paper, Gershman presents and builds upon a reinforcement learning algorithm first proposed by Peter Dayan in 1993, called the successor representation, which solves some important problems that previous classes of reinforcement learning algorithms have had.  Recent research has supported the idea that humans and other animals use successor representations for learning and decision making under some conditions and has proposed that dopaminergic mechanisms could build successor representations in the brain. [Read More]

Customizable, wireless and implantable neural probe design and fabrication via 3D printing. Nature Protocols.

Detailed in this protocol are custom manufacturing techniques for rapidly 3D-printing large number of optogenetic probes of any length and number of shanks. Also included are instructions for low-cost, custom, wireless harnesses to couple with probes for offsite optical manipulation. [Read More]

Insights into distinct signaling profiles of the µOR activated by diverse agonists. Nat Chem Biology.

The TRUPATH BRET2 assay is a single and comprehensive platform of 14 G protein biosensors that allows for unambiguous measurement of heterotrimeric G protein dissociation following agonist-induced receptor stimulation. Because individual G protein subunits have distinct functional characteristics, directly monitoring their activation and signaling profiles provides new opportunities for revealing previously uncharacterized actions of GPCR ligands. [Read More]

Single-Cell Chromatin Modification Profiling Reveals Increased Epigenetic Variations with Aging. Cell.

A group of researchers from Stanford University employed a multiplexed mass cytometry to profile the epigenetic landscape and measure a broad array of global chromatin modifications in human cells at the single-cell level. The EpiTOF technology provides new opportunities for identifying cell-specific epigenetic changes associated with altered physiological and pathological states. [Read More]