Structural basis for substrate flexibility of the O-methyltransferase MpaG' involved in mycophenolic acid biosynthesis.

MpaG' is an S-adenosyl-L-methionine (SAM)-dependent methyltransferase involved in the compartmentalized biosynthesis of mycophenolic acid (MPA), a first-line immunosuppressive drug for organ transplantations and autoimmune diseases. MpaG' catalyzes the 5-O-methylation of three precursors in MPA biosynthesis including demethylmycophenolic acid (DMMPA), 4-farnesyl-3,5-dihydroxy-6-methylphthalide (FDHMP), and an intermediate containing three fewer carbon atoms compared to FDHMP (FDHMP-3C) with different catalytic efficiencies. Here, we report the crystal structures of S-adenosyl-L-homocysteine (SAH)/DMMPA-bound MpaG', SAH/FDHMP-3C-bound MpaG', and SAH/FDHMP-bound MpaG' to understand the catalytic mechanism of MpaG' and structural basis for its substrate flexibility.

Inflammation-Derived and Clinical Indicator-Based Predictive Model for Ischemic Stroke Recovery.

Background: Neuroinflammatory responses are closely associated with poststroke prognosis severity. This study aimed to develop a predictive model, combining inflammation-derived markers and clinical indicators, for distinguishing functional outcomes in patients with subacute ischemic stroke.

Methods And Results: Based on activities of daily living assessments, ischemic stroke participants were categorized into groups with little effective (LE) recovery and obvious effective (OE) recovery.

Surface protein profiling and subtyping of extracellular vesicles in body fluids reveals non-CSF biomarkers of Alzheimer's disease.

Noninvasive and effortless diagnosis of Alzheimer's disease (AD) remains challenging. Here we report the multiplexed profiling of extracellular vesicle (EV) surface proteins at the single EV level in five types of easily accessible body fluids using a proximity barcoding assay (PBA). A total of 183 surface proteins were detected on the EVs from body fluids collected from APP/PS1 transgenic mice and patients with AD.

A cellulosomal double-dockerin module from Clostridium thermocellum shows distinct structural and cohesin-binding features.

Cellulosomes are intricate cellulose-degrading multi-enzymatic complexes produced by anaerobic bacteria, which are valuable for bioenergy development and biotechnology. Cellulosome assembly relies on the selective interaction between cohesin modules in structural scaffolding proteins (scaffoldins) and dockerin modules in enzymes. Although the number of tandem cohesins in the scaffoldins is believed to determine the complexity of the cellulosomes, tandem dockerins also exist, albeit very rare, in some cellulosomal components whose assembly and functional roles are currently unclear.

Forebrain E-I balance controlled in cognition through coordinated inhibition and inhibitory transcriptome mechanism.

Introduction: Forebrain neural networks are vital for cognitive functioning, and their excitatory-inhibitory (E-I) balance is governed by neural homeostasis. However, the homeostatic control strategies and transcriptomic mechanisms that maintain forebrain E-I balance and optimal cognition remain unclear.

Methods: We used patch-clamp and RNA sequencing to investigate the patterns of neural network homeostasis with suppressing forebrain excitatory neural activity and spatial training.

Diversification of phenolic glucosides by two UDP-glucosyltransferases featuring complementary regioselectivity.

Background: Glucoside natural products have been showing great medicinal values and potentials. However, the production of glucosides by plant extraction, chemical synthesis, and traditional biotransformation is insufficient to meet the fast-growing pharmaceutical demands. Microbial synthetic biology offers promising strategies for synthesis and diversification of plant glycosides.

Transcription factor EB coordinates environmental cues to regulate T regulatory cells' mitochondrial fitness and function.

T regulatory (Treg) cells are essential for self-tolerance whereas they are detrimental for dampening the host anti-tumor immunity. How Treg cells adapt to environmental signals to orchestrate their homeostasis and functions remains poorly understood. Here, we identified that transcription factor EB (TFEB) is induced by host nutrition deprivation or interleukin (IL)-2 in CD4 T cells.

Enhancing the nonlinearity of optomechanical system via multiple mechanical modes.

We theoretically investigate the nonlinear dynamics of an optomechanical system, where the system consists of N identical mechanical oscillators individually coupled to a common cavity field. We find that the optomechanical nonlinearity can be enhanced N times through theoretical analysis and numerical simulation in such a system. This leads to the power thresholds to observe the nonlinear behaviors (bistable, period-doubling, and chaotic dynamics) being reduced to 1/N.

Three-component 1,2-carboamination of vinyl boronic esters amidyl radical induced 1,2-migration.

Three-component 1,2-carboamination of vinyl boronic esters with alkyl/aryl lithium reagents and -chloro-carbamates/carboxamides is presented. Vinylboron ate complexes generated from the boronic ester and an organo lithium reagent are shown to react with readily available -chloro-carbamates/carboxamides to give valuable 1,2-aminoboronic esters. These cascades proceed in the absence of any catalyst upon simple visible light irradiation.

Metformin attenuates hypothalamic inflammation via downregulation of RIPK1-independent microglial necroptosis in diet-induced obese mice.

Necroptosis, a form of programmed cell death, accounts for many inflammations in a wide range of diseases. Diet-induced obesity is manifested by low-grade inflammation in the mediobasal hypothalamus (MBH), and microglia are implicated as critical responsive components for this process. Here, we demonstrate that microglial necroptosis plays a pivotal role in obesity-related hypothalamic inflammation, facilitating proinflammatory cytokine production, such as TNF-α and IL-1β.

Unexpected Reactions of α,β-Unsaturated Fatty Acids Provide Insight into the Mechanisms of CYP152 Peroxygenases.

CYP152 peroxygenases catalyze decarboxylation and hydroxylation of fatty acids using H O as cofactor. To understand the molecular basis for the chemo- and regioselectivity of these unique P450 enzymes, we analyze the activities of three CYP152 peroxygenases (OleT , P450 , P450 ) towards cis- and trans-dodecenoic acids as substrate probes. The unexpected 6S-hydroxylation of the trans-isomer and 4R-hydroxylation of the cis-isomer by OleT , and molecular docking results suggest that the unprecedented selectivity is due to OleT 's preference of C2-C3 cis-configuration.

Biosynthesis of Chuangxinmycin Featuring a Deubiquitinase-like Sulfurtransferase.

The knowledge on sulfur incorporation mechanism involved in sulfur-containing molecule biosynthesis remains limited. Chuangxinmycin is a sulfur-containing antibiotic with a unique thiopyrano[4,3,2-cd]indole (TPI) skeleton and selective inhibitory activity against bacterial tryptophanyl-tRNA synthetase. Despite the previously reported biosynthetic gene clusters and the recent functional characterization of a P450 enzyme responsible for C-S bond formation, the enzymatic mechanism for sulfur incorporation remains unknown.

Regio- and Stereoselective 1,2-Carboboration of Ynamides with Aryldichloroboranes.

Catalyst-free 1,2-carboboration of ynamides is presented. Readily available aryldichloroboranes react with alkyl- or aryl-substituted ynamides in high yields with complete regio- and stereoselectivity to valuable β-boryl-β-alkyl/aryl α-aryl substituted enamides which belong to the class of trisubstituted alkenylboronates. The 1,2-carboboration reaction is experimentally easy to conduct, shows high functional group tolerance and broad substrate scope.

Structural basis for substrate specificity of the peroxisomal acyl-CoA hydrolase MpaH' involved in mycophenolic acid biosynthesis.

Mycophenolic acid (MPA) is a fungal natural product and first-line immunosuppressive drug for organ transplantations and autoimmune diseases. In the compartmentalized biosynthesis of MPA, the acyl-coenzyme A (CoA) hydrolase MpaH' located in peroxisomes catalyzes the highly specific hydrolysis of MPA-CoA to produce the final product MPA. The strict substrate specificity of MpaH' not only averts undesired hydrolysis of various cellular acyl-CoAs, but also prevents MPA-CoA from further peroxisomal β-oxidation catabolism.

Structural Basis for Selective Oxidation of Phosphorylated Ethylphenols by Cytochrome P450 Monooxygenase CreJ.

Selective oxidation of C-H bonds in alkylphenols holds great significance for not only structural derivatization in pharma- and biomanufacturing but also biological degradation of these toxic chemicals in environmental protection. A unique chemomimetic biocatalytic system using enzymes from a -cresol biodegradation pathway has recently been developed. As the central biocatalyst, the cytochrome P450 monooxygenase CreJ oxidizes diverse - and -alkylphenol phosphates with perfect stereoselectivity at different efficiencies.

Nickel-Catalyzed Asymmetric Hydrogenation of Cyclic Alkenyl Sulfones, Benzo[]thiophene 1,1-Dioxides, with Mechanistic Studies.

A highly efficient catalytic system based on the cheap transition metal nickel for the asymmetric hydrogenation of challenging cyclic alkenyl sulfones, 3-substituted benzo[]thiophene 1,1-dioxides, was first successfully developed. A series of hydrogenation products, chiral 2,3-dihydrobenzo[]thiophene 1,1-dioxides, were obtained in high yields (95-99%) with excellent enantioselectivities (90-99% ee). According to the results of nonlinear effect studies, deuterium-labeling experiments, and DFT calculation investigations, a reasonable catalytic mechanism for this nickel-catalyzed asymmetric hydrogenation was provided, which displayed that the two added hydrogen atoms of the hydrogenation products could be from H through the insertion of Ni-H and subsequent hydrogenolysis.

Synthesis of 1,3-Bis-(boryl)alkanes through Boronic Ester Induced Consecutive Double 1,2-Migration.

A general and efficient approach for the preparation of 1,3-bis-(boryl)alkanes is introduced. It is shown that readily generated vinylboron ate complexes react with commercially available ICH Bpin to valuable 1,3-bis-(boryl)alkanes. The introduced transformation, which is experimentally easy to conduct, shows broad substrate scope and high functional-group tolerance.

Asymmetric Linear-Selective Hydroformylation of 1,1-Dialkyl Olefins Assisted by a Steric-Auxiliary Strategy.

Asymmetric hydroformylation of 1,2-dialkyl olefins was reported. In order to increase the enantiomeric induction, steric auxiliary sulfonyl groups were introduced. Using a Rh/Yanphos complex as catalyst, chiral aldehydes were obtained with high enantioselectivities under mild pressure.

Rhodium-catalyzed asymmetric hydrogenation of exocyclic α,β-unsaturated carbonyl compounds.

A highly enantioselective hydrogenation of exocyclic α,β-unsaturated carbonyl compounds catalyzed by Rh/bisphosphine-thiourea (ZhaoPhos) has been developed, giving the corresponding α-chiral cyclic lactones, lactams and ketones with high yields and excellent enantioselectivities (up to 99% yield and 99% ee). Remarkably, the hydrogen bond between the substrate and the catalyst plays a critical role in this transformation. The synthetic utility of this protocol has been demonstrated by efficient synthesis of chiral 3-(4-fluorobenzyl)piperidine, a key chiral fragment of bioactive molecules.

Rhodium-Catalyzed Enantioselective Anti-Markovnikov Hydroformylation of α-Substituted Acryl Acid Derivatives.

Rhodium-catalyzed asymmetric anti-Markovnikov hydroformylation of α-substituted acrylates/acrylamides has been developed. By employing the Rh/(,)-DTBM-YanPhos complex, a series of β-chiral linear aldehydes were obtained in high yields (up to 94% yield) and high enantioselectivities (up to 96% ee). The utility of this methodology is demonstrated by a gram-scale reaction and a concise synthetic route to chiral γ-butyrolactone.

Nanoparticle-mediated chiral light chaos based on non-Hermitian mode coupling.

Non-Hermitian physics basically due to the interplay between gain and loss has attracted considerable attention in the context of understanding various brand-new and counterintuitive physical phenomena. The major emphasis of this work is concerned with the chirality properties of chaotic motion in a whispering-gallery-mode microresonator based on nanoparticle-induced non-Hermitian mode coupling, which will be a challenging endeavor that is rarely presented in previous literature. By operating the nanoparticles in a whispering-gallery-mode microresonator, we achieved a dynamic control of chaotic behavior, and a rather more exotic finding is that the chaotic motion features chiral characteristics.

Transcriptome Sequencing Unravels Potential Biomarkers at Different Stages of Cerebral Ischemic Stroke.

Ischemic stroke, which accounts for 87% of all strokes, constitutes the leading cause of morbidity and mortality in China. Although the genetics and epigenetics of stroke have been extensively investigated, few studies have examined their relationships at different stages of stroke. This study assessed the characteristics of transcriptome changes at different stages of ischemic stroke using a mouse model of transient middle cerebral artery occlusion (tMCAO) and bioinformatics analyses.

Slow Dynamics of the Spin-Crossover Process in an Apparent High-Spin Mononuclear Fe Complex.

A mononuclear Fe complex that shows a high-spin (S=2) paramagnetic behavior at all temperatures (with standard temperature-scan rates, ≈1 K min ) has, in fact, a low-spin (S=0) ground state below 100 K. This low-spin state is not easily accessible due to the extremely slow dynamics of the spin-crossover process-a full relaxation from the metastable high-spin state to the low-spin ground state takes more than 5 h below 80 K. Bidirectional photo-switching of the Fe state is achieved reproducibly by two selective irradiations (at 530-590 and 830-850 nm).

Nickel-Catalyzed Desymmetric Hydrogenation of Cyclohexadienones: An Efficient Approach to All-Carbon Quaternary Stereocenters.

Nickel-catalyzed desymmetric hydrogenation has been achieved. With the Ni(OTf)/(,)-Ph-BPE system, a series of γ,γ-disubstituted cyclohexadienones were transformed to the corresponding cyclohexenones with a chiral all-carbon quaternary center at the γ position in high yields (92-98%) and excellent enantioselectivities (92%-99% ee). This catalytic system can also tolerate the desymmetric reaction of spirocarbocyclic cyclohexadienones to produce the corresponding cyclohexenones bearing a chiral spiro quaternary carbon with high yields (94%-98%) and ee values (96%-99% ee).

Differentially expressed circular RNAs in maternal and neonatal umbilical cord plasma from SGA compared with AGA.

Small for gestational age (SGA) has a high risk of mortality and morbidity and is common in obstetrics. To date, no effective prediction and treatment tools are available. Acting as microRNA (miRNA) sponges and disease biomarkers are clear functions of circular RNAs (circRNAs).