Insights into E.†coli Cyclopropane Fatty Acid Synthase (CFAS) Towards Enantioselective Carbene Free Biocatalytic Cyclopropanation.

Cyclopropane fatty acid synthases (CFAS) are a class of S-adenosylmethionine (SAM) dependent methyltransferase enzymes able to catalyse the cyclopropanation of unsaturated phospholipids. Since CFAS enzymes employ SAM as a methylene source to cyclopropanate alkene substrates, they have the potential to be mild and more sustainable biocatalysts for cyclopropanation transformations than current carbene-based approaches. This work describes the characterisation of E. coli CFAS (ecCFAS) and its exploitation in the stereoselective biocatalytic synthesis of cyclopropyl lipids. ecCFAS was found to convert phosphatidylglycerol (PG) to methyl dihydrosterculate 1 with up to 58 % conversion and 73 % ee and the absolute configuration (9S,10R) was established. Substrate tolerance of ecCFAS was found to be correlated with the electronic properties of phospholipid headgroups and for the first time ecCFAS was found to catalyse cyclopropanation of both phospholipid chains to form dicyclopropanated products. In addition, mutagenesis and in silico experiments were carried out to identify the enzyme residues with key roles in catalysis and to provide structural insights into the lipid substrate preference of ecCFAS. Finally, the biocatalytic synthesis of methyl dihydrosterculate 1 and its deuterated analogue was also accomplished combining recombinant ecCFAS with the SAM regenerating AtHMT enzyme in the presence of CH3I and CD3I respectively.

E3 Ubiquitin Ligase Uhrf2 Knockout Reveals a Critical Role in Social Behavior and Synaptic Plasticity in the Hippocampus.

The hippocampal formation, particularly the CA2 subregion, is critical for social memory formation and memory processing, relying on synaptic plasticity-a fundamental mechanism by which synapses strengthen. Given the role of the ubiquitin-proteasome system (UPS) in various nervous system processes, including learning and memory, we were particularly interested in exploring the involvement of RING-type ubiquitin E3 ligases, such as UHRF2 (NIRF), in social behavior and synaptic plasticity. Our results revealed altered social behavior in mice with systemic Uhrf2 knockout, including changes in nest building, tube dominance, and the three-chamber social novelty test. In Uhrf2 knockout mice, the entorhinal cortex-CA2 circuit showed significant reductions in synaptic plasticity during paired-pulse facilitation and long-term potentiation, while the inability to evoke synaptic plasticity in the Schaffer-collateral CA2 synapses remained unaffected. These changes in synaptic plasticity correlated with significant changes in gene expression including genes related to vesicle trafficking and transcriptional regulation. The effects of Uhrf2 knockout on synaptic plasticity and the observed gene expression changes highlight UHRF2 as a regulator of learning and memory processes at both the cellular and systemic levels. Targeting E3 ubiquitin ligases, such as UHRF2, may hold therapeutic potential for memory-related disorders, warranting further investigation.

Apoptosis signal-regulating kinase 1 (Ask1) deficiency alleviates MPP+-induced impairment of evoked dopamine release in the mouse hippocampus.

The dopaminergic system is susceptible to dysfunction in numerous neurological diseases, including Parkinson's disease (PD). In addition to motor symptoms, some PD patients may experience non-motor symptoms, including cognitive and memory deficits. A possible explanation for their manifestation is a disturbed pattern of dopamine release in brain regions involved in learning and memory, such as the hippocampus. Therefore, investigating neuropathological alterations in dopamine release prior to neurodegeneration is imperative. This study aimed to characterize evoked hippocampal dopamine release and assess the impact of the neurotoxin MPP+ using a genetically encoded dopamine sensor and gene expression analysis. Additionally, considering the potential neuroprotective attributes demonstrated by apoptosis signal-regulating kinase 1 (Ask1) in various animal-disease-like models, the study also aimed to determine whether Ask1 knockdown restores MPP+-altered dopamine release in acute hippocampal slices. We applied variations of low- and high-frequency stimulation to evoke dopamine release within different hippocampal regions and discovered that acute application of MPP+ reduced the amount of dopamine released and hindered the recovery of dopamine release after repeated stimulation. In addition, we observed that Ask1 deficiency attenuated the detrimental effects of MPP+ on the recovery of dopamine release after repeated stimulation. RNA sequencing analysis indicated that genes associated with the synaptic pathways are involved in response to MPP+ exposure. Notably, Ask1 deficiency was found to downregulate the expression of Slc5a7, a gene encoding a sodium-dependent high-affinity choline transporter that regulates acetylcholine levels. Respective follow-up experiments indicated that Slc5a7 plays a role in Ask1 deficiency-mediated protection against MPP+ neurotoxicity. In addition, increasing acetylcholine levels using an acetylcholinesterase inhibitor could exacerbate the toxicity of MPP+. In conclusion, our data imply that the modulation of the dopamine-acetylcholine balance may be a crucial mechanism of action underlying the neuroprotective effects of Ask1 deficiency in PD.

Feedback regulation of plant secondary metabolism: Applications and challenges.

Plant secondary metabolites offer resistance to invasion by herbivorous organisms, and are also useful in the chemical, pharmaceutical, cosmetic, and fragrance industries. There are numerous approaches to enhancing secondary metabolite yields. However, a growing number of studies has indicated that feedback regulation may be critical in regulating secondary metabolite biosynthesis. Here, we review examples of feedback regulation in secondary metabolite biosynthesis pathways, phytohormone signal transduction, and complex deposition sites associated with secondary metabolite biosynthesis. We propose a new strategy to enhance secondary metabolite production based on plant feedback regulation. We also discuss challenges in feedback regulation that must be overcome before its application to enhancing secondary metabolite yields. This review discusses recent advances in the field and highlights a strategy to overcome feedback regulation-related obstacles and obtain high secondary metabolite yields.

Treatment effect of exercise training on post-stroke depression in middle-aged and older adults: A meta-analysis.

OBJECTIVE: This meta-analytic study examined the effects of exercise training on depressive symptoms in mild stroke patients and the moderating effects of exercise type, therapeutic method, culture, sex, and gross domestic product (GDP) in the patient's country. METHODS: The Metafor package in R was chosen to conduct the meta-analysis, and the quality of each empirical study was evaluated according to the grading system in Cochrane. We included 36 empirical studies and 1477 patients. RESULTS: The results showed that the treatment effect of exercise training on depression in mild stroke patients was significant. The moderating effects of culture and therapeutic method were significant, but not for exercise type, sex, or GDP in the patient's country. The moderating effect of culture can be explained by the therapeutic method in different cultures. CONCLUSION: Fitness exercise is an effective method for improving depressive symptoms in mild stroke patients. Its effectiveness is moderated by the therapeutic method but is not affected by demographics, exercise type, gender, or GDP level.

Realizing Sub-5 nm Red Phosphorus Dispersion in a SiOx/C Matrix for Enhanced Lithium Storage.

With high capacity and suitable working plateau, silicon oxide (SiOx) has become a promising lithium-ion battery (LIB) anode material. However, bare SiOx usually suffers from sluggish electron transport and unsatisfactory cyclability. Composting SiOx with a second phase has become an efficient strategy to tackle the current drawbacks. Herein, a P/SiOx/C ternary composite, featuring sub-5 nm red phosphorus (P) clusters uniformly dispersed in a dense SiOx/C matrix has been constructed through an "inside-out" synthesis strategy. The nanosizing of bulk red P sealed in an organosilica matrix is realized by the high-temperature treatment-driven sublimation/diffusion. With the red P amount of ∼7.53 wt %, the P/SiOx/C ternary composite provides a stable discharge capacity of ∼950 mAh g-1 and also manifests a decent rate capability (510 mAh g-1 at 5 A g-1). This study affords a ternary compositing strategy for designing SiOx-based anode materials with desirable electrochemical performance for the next-generation LIBs.

H-BPin/KOtBu Promoted Activation of Cobalt Salt to a Heterotopic Catalyst for Highly Selective Cyclotrimerization of Alkynes.

A mixture of HBPin with KOtBu was found to activate cobalt salt to form a heterotopic cobalt species that is highly active for catalytic intermolecular trimerization of alkynes. This protocol affords 1,2,4-regioisomers in good yields with high regioselectivities under mild conditions. These salient features, together with the operational simplicity and high efficiency, as well as obviating the use of any costly and/or air sensitive ligands, renders the protocol promising for practical applications.

Selective hydroboration of unsaturated bonds by an easily accessible heterotopic cobalt catalyst.

Homogeneous earth-abundant metal catalysis based on well-defined molecular complexes has achieved great advance in synthetic methodologies. However, sophisticated ligand, hazardous activator and multistep synthesis starting from base metal salts are generally required for the generation of active molecular catalysts, which may hinder their broad application in large scale organic synthesis. Therefore, the development of metal cluster catalysts formed in situ from simple earth-abundant metal salts is of importance for the practical utilization of base metal resource, yet it is still in its infancy. Herein, a mixture of catalytic amounts of cobalt (II) iodide and potassium tert-butoxide is discovered to be highly active for selective hydroboration of vinylarenes and dihydroboration of nitriles, affording a good yield of diversified hydroboration products that without isolation can readily undergo further one pot transformations. It should be highlighted that the alkoxide-pinacolborane combination acts as an efficient activation strategy to activate cobalt (II) iodide for the generation of metastable heterotopic cobalt catalysts in situ, which is proposed to be catalytically active species.

Positive Regulatory Domain I-binding Factor 1 Mediates Peripheral Nerve Injury-induced Nociception in Mice by Repressing Kv4.3 Channel Expression.

BACKGROUND: The transcriptional repressor positive regulatory domain I-binding factor 1 (PRDM1) is expressed in adult mouse dorsal root ganglion and regulates the formation and function of peripheral sensory neurons. The authors hypothesized that PRDM1 in the dorsal root ganglion may contribute to peripheral nerve injury-induced nociception regulation and that its mechanism may involve Kv4.3 channel transcriptional repression. METHODS: Nociception was induced in C57BL/6 mice by applying chronic constriction injury, complete Freund's adjuvant, or capsaicin plantar injection. Nociceptive response was evaluated by mechanical allodynia, thermal hyperalgesia, cold hyperalgesia, or gait analysis. The role of PRDM1 was evaluated by injection of Prdm1 knockdown and overexpression adeno-associated viruses. The interaction of PRDM1 at the Kv4.3 (Kcnd3) promoter was evaluated by chromatin immunoprecipitation assay. Excitability of dorsal root ganglion neurons was evaluated by whole cell patch clamp recordings, and calcium signaling in spinal dorsal horn neurons was evaluated by in vivo two-photon imaging. RESULTS: Peripheral nerve injury increased PRDM1 expression in the dorsal root ganglion, which reduced the activity of the Kv4.3 promoter and repressed Kv4.3 channel expression (injured vs. uninjured; all P < 0.001). Knockdown of PRDM1 rescued Kv4.3 expression, reduced the high excitability of injured dorsal root ganglion neurons, and alleviated peripheral nerve injury-induced nociception (short hairpin RNA vs. Scram; all P < 0.05). In contrast, PRDM1 overexpression in naive mouse dorsal root ganglion neurons diminished Kv4.3 channel expression and induced hyperalgesia (PRDM1 overexpression vs. control, mean ± SD; n = 13; all P < 0.0001) as evaluated by mechanical allodynia (0.6 ± 0.3 vs. 1.2 ± 0.2 g), thermal hyperalgesia (5.2 ± 1.3 vs. 9.8 ± 1.7 s), and cold hyperalgesia (3.4 ± 0.5 vs. 5.3 ± 0.6 s). Finally, PRDM1 downregulation in naive mice reduced the calcium signaling response of spinal dorsal horn neurons to thermal stimulation. CONCLUSIONS: PRDM1 contributes to peripheral nerve injury-induced nociception by repressing Kv4.3 channel expression in injured dorsal root ganglion neurons.

Differential effects of fearful faces under spatial attended and unattended conditions: evidence from an event-related potential study.

We examined the influence of spatial selective attention on the processing of emotional faces (happy neutral, and fear) using behavioral as well as event-related potential recordings. Emotional stimuli were rapidly presented randomly to the right or the left visual field while participants attended to one visual field at a time, detecting smaller stimuli that were shown in the attended field. Behavioral results showed decreased accuracy for the fearful faces compared with neutral and happy faces. Event-related potential data showed that compared with the neutral and happy faces, fearful faces appearing in the right visual field elicited enhanced contralateral P1 amplitudes in the unattended condition, whereas fearful faces appearing in the left visual field elicited decreased contralateral N170 activity in the attended condition. These findings provide evidence for differential emotional processing under spatial attended and unattended conditions.

Prediction of Conversion from Mild Cognitive Impairment to Alzheimer's Disease Using MRI and Structural Network Features.

Optimized magnetic resonance imaging (MRI) features and abnormalities of brain network architectures may allow earlier detection and accurate prediction of the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). In this study, we proposed a classification framework to distinguish MCI converters (MCIc) from MCI non-converters (MCInc) by using a combination of FreeSurfer-derived MRI features and nodal features derived from the thickness network. At the feature selection step, we first employed sparse linear regression with stability selection, for the selection of discriminative features in the iterative combinations of MRI and network measures. Subsequently the top K features of available combinations were selected as optimal features for classification. To obtain unbiased results, support vector machine (SVM) classifiers with nested cross validation were used for classification. The combination of 10 features including those from MRI and network measures attained accuracies of 66.04, 76.39, 74.66, and 73.91% for mixed conversion time, 6, 12, and 18 months before diagnosis of probable AD, respectively. Analysis of the diagnostic power of different time periods before diagnosis of probable AD showed that short-term prediction (6 and 12 months) achieved more stable and higher AUC scores compared with long-term prediction (18 months), with K-values from 1 to 30. The present results suggest that meaningful predictors composed of MRI and network measures may offer the possibility for early detection of progression from MCI to AD.