A chimeric membrane enzyme and an engineered whole-cell biocatalyst for efficient 1-alkene production.

Bioproduction of 1-alkenes from naturally abundant free fatty acids offers a promising avenue toward the next generation of hydrocarbon-based biofuels and green commodity chemicals. UndB is the only known membrane-bound 1-alkene-producing enzyme, with great potential for 1-alkene bioproduction, but the enzyme exhibits limited turnovers, thus restricting its widespread usage. Here, we explore the molecular basis of the limitation of UndB activity and substantially improve its catalytic power.

Functional production and biochemical investigation of an integral membrane enzyme for olefin biosynthesis.

Integral membrane enzymes play essential roles in a plethora of biochemical processes. The fatty acid desaturases (FADS)-like superfamily is an important group of integral membrane enzymes that catalyze a wide array of reactions, including hydroxylation, desaturation, and cyclization; however, due to the membrane-bound nature, the majority of these enzymes have remained poorly understood. UndB is a member of the FADS-like superfamily, which catalyzes fatty acid decarboxylation, a chemically challenging reaction at the membrane interface.

Acetylcholine Structure-Based Small Activatable Fluorogenic Probe for Specific Detection of Acetylcholinesterase.

Early detection of Alzheimer's disease (AD) is important for taking proper measures against AD pathogenesis. Acetylcholinesterase (AChE) is widely reported to be associated with the pathogenicity of AD. Here, employing the "acetylcholine-mimic" approach, we designed and synthesized a new class of naphthalimide (Naph)-based fluorogenic probes for specific detection of AChE and avoiding interference of butyrylcholinesterase (BuChE), the pseudocholinesterase.

Biochemical Investigation of Membrane-Bound Cytochrome b5 and the Catalytic Domain of Cytochrome b5 Reductase from .

The endoplasmic reticulum (ER) membrane of plant cells contains several enzymes responsible for the biosynthesis of a diverse range of molecules essential for plant growth and holds potential for industrial applications. Many of these enzymes are dependent on electron transfer proteins to sustain their catalytic cycles. In plants, two crucial ER-bound electron transfer proteins are cytochrome b5 and cytochrome b5 reductase, which catalyze the stepwise transfer of electrons from NADH to redox enzymes such as fatty acid desaturases, cytochrome P450s, and plant aldehyde decarbonylase.

Metalloenzymes for Fatty Acid-Derived Hydrocarbon Biosynthesis: Nature's Cryptic Catalysts.

Waning resources, massive energy consumption, ever-deepening global warming crisis, and climate change have raised grave concerns regarding continued dependence on fossil fuels as the predominant source of energy and generated tremendous interest for developing biofuels, which are renewable. Hydrocarbon-based 'drop-in' biofuels can be a proper substitute for fossil fuels such as gasoline or jet fuel. In Nature, hydrocarbons are produced by diverse organisms such as insects, plants, bacteria, and cyanobacteria.

Identification of an optimal dose of intravenous ketamine for late-life treatment-resistant depression: a Bayesian adaptive randomization trial.

Evidence supporting specific therapies for late-life treatment-resistant depression (LL-TRD) is necessary. This study used Bayesian adaptive randomization to determine the optimal dose for the probability of treatment response (≥50% improvement from baseline on the Montgomery-Åsberg Depression Rating Scale) 7 days after a 40 min intravenous (IV) infusion of ketamine 0.1 mg/kg (KET 0.

Neurophysiological and clinical effects of the NMDA receptor antagonist lanicemine (BHV-5500) in PTSD: A randomized, double-blind, placebo-controlled trial.

Background: Posttraumatic stress disorder (PTSD) is associated with hyperarousal and stress reactivity, features consistent with behavioral sensitization. In this Phase 1b, parallel-arm, randomized, double-blind, placebo-controlled trial, we tested whether the selective low-trapping N-methyl-D-aspartate receptor (NMDAR) antagonist [Lanicemine (BHV-5500)] blocks expression of behavioral sensitization.

Methods: Twenty-four participants with elevated anxiety potentiated startle (APS) and moderate-to-severe PTSD symptoms received three infusions of lanicemine 1.

Does mismatch negativity have utility for NMDA receptor drug development in depression?

Rapid antidepressant effects associated with ketamine have shifted the landscape for the development of therapeutics to treat major depressive disorder (MDD) from a monoaminergic to glutamatergic model. Treatment with ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may be effective, but has many non-glutamatergic targets, and clinical and logistical problems are potential challenges. These factors underscore the importance of manipulations of binding mechanics to produce antidepressant effects without concomitant clinical side effects.

Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial.

Objective: Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression.

Methods: Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24).

A Proof-of-Mechanism Study to Test Effects of the NMDA Receptor Antagonist Lanicemine on Behavioral Sensitization in Individuals With Symptoms of PTSD.

Individuals with post-traumatic stress disorder (PTSD) have a heightened sensitivity to subsequent stressors, addictive drugs, and symptom recurrence, a form of behavioral sensitization. N-methyl-D-aspartate receptors (NMDARs) are involved in the establishment and activation of sensitized behavior. We describe a protocol of a randomized placebo-controlled Phase 1b proof-of-mechanism trial to examine target engagement, safety, tolerability, and possible efficacy of the NMDAR antagonist lanicemine in individuals with symptoms of PTSD (Clinician Administered PTSD Scale [CAPS-5] score ≥ 25) and evidence of behavioral sensitization measured as enhanced anxiety-potentiated startle (APS; T-score ≥ 2.

Bayesian adaptive randomization trial of intravenous ketamine for veterans with late-life, treatment-resistant depression.

More than eleven million U.S. Veterans are at least 65 years of age, an age group of which almost 20% suffers from clinically significant depressive symptoms.

Elucidating the Inhibitory Potential of Designed Peptides Against Amyloid Fibrillation and Amyloid Associated Cytotoxicity.

Inhibition of fibrillation process and disaggregation of mature fibrils using small peptide are the promising remedial strategies to combat neurodegenerative diseases. However, designing peptide-based drugs to target β-sheet-rich amyloid has been a major challenge. The current work describes, for the first time, the amyloid inhibitory potential of the two short peptides (selected on the basis of predisposition of their amino acid residues toward β-sheet formation) using combination of biophysical, imaging methods, and docking approaches.

The relationship between sleep and drug use characteristics in participants with cocaine or methamphetamine use disorders.

The goal of this project was to evaluate the relationship between self-reported sleep habits, daytime sleepiness, and drug use variables in individuals with cocaine and methamphetamine (METH) use disorders. Participants with a cocaine or meth use disorder completed questionnaires, including the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and a demographic/drug use form. Participants with a cocaine (N=51) or meth use disorder (N=85) were separated into those with either high or low sleep deficits.