Ketogenic Diets Alter the Gut Microbiome, Resulting in Decreased Susceptibility to and Cognitive Impairment in Rats with Pilocarpine-Induced Status Epilepticus.

A ketogenic diet (KD) is a high-fat, low-carbohydrate, and low-protein diet that exerts antiepileptic effects by attenuating spontaneous recurrent seizures, ameliorating learning and memory impairments, and modulating the gut microbiota composition. However, the role of the gut microbiome in the antiepileptic effects of a KD on temporal lobe epilepsy (TLE) induced by lithium-pilocarpine in adult rats is still unknown. Our study provides evidence demonstrating that a KD effectively mitigates seizure behavior and reduces acute-phase epileptic brain activity and that KD treatment alleviates hippocampal neuronal damage and improves cognitive impairment induced by TLE. We also observed that the beneficial effects of a KD are compromised when the gut microbiota is disrupted through antibiotic administration. Analysis of gut microbiota components via 16S rRNA gene sequencing in fecal samples collected from TLE rats fed either a KD or a normal diet. The Chao1 and ACE indices showed decreased species variety in KD-fed rats compared to TLE rats fed a normal diet. A KD increased the levels of Actinobacteriota, Verrucomicrobiota and Proteobacteria and decreased the level of Bacteroidetes. Interestingly, the abundances of Actinobacteriota and Verrucomicrobiota were positively correlated with learning and memory ability, and the abundance of Proteobacteria was positively correlated with seizure susceptibility. In conclusion, our study revealed the significant antiepileptic and neuroprotective effects of a KD on pilocarpine-induced epilepsy in rats, primarily mediated through the modulation of the gut microbiota. However, whether the gut microbiota mediates the antiseizure effects of a KD still needs to be better elucidated.

Exploration of cell type-specific somatic mutations in schizophrenia and the impact of maternal immune activation on the somatic mutation profile in the brain.

AIM: Schizophrenia (SZ) is a severe psychiatric disorder caused by the interaction of genetic and environmental factors. Although somatic mutations that occur in the brain after fertilization may play an important role in the cause of SZ, their frequencies and patterns in the brains of patients and related animal models have not been well studied. This study aimed to find somatic mutations related to the pathophysiology of SZ. METHODS: We performed whole-exome sequencing (WES) of neuronal and nonneuronal nuclei isolated from the postmortem prefrontal cortex of patients with SZ (n = 10) and controls (n = 10). After detecting somatic mutations, we explored the similarities and differences in shared common mutations between two cell types and cell type-specific mutations. We also performed WES of prefrontal cortex samples from an animal model of SZ based on maternal immune activation (MIA) and explored the possible impact of MIA on the patterns of somatic mutations. RESULTS: We did not find quantitative differences in somatic mutations but found higher variant allele fractions of neuron-specific mutations in patients with SZ. In the mouse model, we found a larger variation in the number of somatic mutations in the offspring of MIA mice, with the occurrence of somatic mutations in neurodevelopment-related genes. CONCLUSION: Somatic mutations occurring at an earlier stage of brain cell differentiation toward neurons may be important for the cause of SZ. MIA may affect somatic mutation profiles in the brain.

Infrared spectra of the SARS-CoV-2 spike receptor-binding domain: Molecular dynamics simulations.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread around the world rapidly, which seriously threatens to human health and safety. The rapid detection of the virus in the early stage is very important to prevent the cross infection and transmission. It is also a key link in the post-treatment examination. This paper has explored the infrared (IR) spectra of spike protein receptor-binding domain (RBD) for SARS-CoV-2 using molecular dynamics simulations, and the absorption bands are assigned. The calculated IR spectra of water and insulin are compared with that measured in the related literatures. The results showed that O-H stretching vibration generated a strong absorption band located around 3591 cm-1, the oscillator strength of 310 K is slightly higher than that at 298 K. The absorption peaks have a small red shift or blue shift with the change of temperature. As a theoretical basis for the optical detection of SARS-CoV-2 virus, this work will play a positive role in promoting the development of new virus detection technology.

ROS triggered local delivery of stealth exosomes to tumors for enhanced chemo/photodynamic therapy.

BACKGROUND: Exosomes are recognized as effective platforms for targeted delivery for their high physicochemical stability and biocompatibility. However, most of the exosomes are inevitably and rapidly cleared by mononuclear phagocytic system (MPS) during cancer therapy. How to engineer exosome to enhance the delivery efficiency is being intensively explored. In this study, we have constructed mPEG2000-TK-CP05 decorated exosomes as effective delivery platforms to achieve enhanced photodynamic/chemical cancer therapy. RESULTS: Exosomes were coated with CP05-TK-mPEG2000, in which CP05 is a peptide with high affinity to exosomal CD63 and TK could be cleaved by ROS. The resulted exosomes, namely stealth Exo, were electroporated to load RB (photosensitizer Rose Bengal) and Dox (Doxorubicin). We verified that the Stealth Exo@RB (Stealth Exo additionally loaded with RB) could escape MPS while accumulate in the tumor region efficiently in the xenograft model when laser irradiation conducted locally. Additionally, we revealed that the Stealth Exo serves as an efficient platform for Dox delivery. Dox, together with the RB mediated photodynamic therapy induce tumor cell damage synergistically in the tumor region. Moreover, the proposed switchable stealth exosomes minimized the dose of toxic Dox and thus allowed robust tumor immune response. CONCLUSIONS: Our results indicated that the proposed Stealth Exo greatly improves both the accessibility and efficiency of drug delivery, with minimal chemical or genetic engineering. The proposed Stealth Exo serve as a promising and powerful drug delivery nanoplatform in cancer treatment.

Insights into the conformation changes of SARS-CoV-2 spike receptor-binding domain on graphene.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been widely spread in the world, causing more than two million deaths and seriously threatening human life. Effective protection measures are important to prevent the infection and spreading of the virus. To explore the effects of graphene on the virus adsorption and its biological properties, the adsorption process of the receptor binding domain (RBD) of SARS-CoV-2 on graphene has been investigated by molecular dynamics simulations in this paper. The results show that RBD can be quickly adsorbed onto the surface of graphene due to π - π stacking and hydrophobic interactions. Residue PHE486 with benzene ring has stronger adsorption force and the maximum contact area with graphene. Graphene significantly affects the secondary structure of RBD area, especially on the three key sites of binding with human ACE2, GLY476, PHE486 and ASN487. The binding free energy of RBD and graphene shows that the adsorption is irreversible. Undoubtedly, these changes will inevitably affect the pathogenicity of the virus. Therefore, this study provides a theoretical basis for the application of graphene in the protection of SARS-CoV-2, and also provides a reference for the potential application of graphene in the biomedical field.

Efficacy of anticonvulsant ethosuximide for major depressive disorder: a randomized, placebo-control clinical trial.

Results of a preclinical study suggested that the anticonvulsant drug ethosuximide may elicit ketamine-like rapid-acting antidepressant actions. We evaluated the antidepressant efficacy of ethosuximide versus placebo in non-medicated adult patients with major depressive disorder (MDD). This randomized, double-blind, placebo-controlled trial included patients at three mental health centers in China. Eighty eligible adults (aged 18-65 years) met the DSM-5 criteria for MDD. Patients in the acute single study received three doses (500, 1000, or 1500 mg) of ethosuximide or placebo. Patients in the repeated study received ethosuximide (1500 mg/day) or placebo for 2 weeks. The Hamilton Depression Rating Scale (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Hamilton Anxiety Rating Scale were used to assess antidepressant and antianxiety responses to ethosuximide. No significant reductions in depression and anxiety rating scale scores were observed after a single oral administration of ethosuximide, in comparison with placebo. Furthermore, patients receiving ethosuximide for 2 weeks did not show reductions in depression and anxiety rating scale scores. There were no serious adverse events. Responses to the study's primary and secondary outcome measures, the clinician-rated HAM-D and MADRS, showed no change from baseline to the end of treatment, with either ethosuximide or placebo. These results suggest that ethosuximide does not produce ketamine-like robust antidepressant actions in adult patients with MDD.

Nuclear Factor κB/MicroRNA-155 Upregulates the Expression Pattern of Cytokines in Regulating the Relapse of Chronic Sinusitis with Nasal Polyps and the Underlying Mechanism of Glucocorticoid.

BACKGROUND The aim of this study was to explore the upregulated nuclear factor kappaB (NF-kappaB)/microRNA-155 (miR-155) in regulating inflammatory responses and relapse of chronic rhinosinusitis (CRS) with nasal polyps (NP), which underlies the molecular mechanism of glucocorticoid treatment. MATERIAL AND METHODS The study recruited 25 patients with eosinophilic (Eos) CRSwNP, 25 patients with Non-Eos CRSwNP, 25 patients with CRS without NP (CRSsNP) and 30 patients with nasal septum deviation (control group). The expression of NF-kappaB/miR-155 and inflammatory cytokines was detected in epithelial tissue specimens. Additionally, a mouse model of Eos CRSwNP was established, and the mice were treated by NF-kappaB inhibitor, miR-155 antagomir, or dexamethasone (DEX) to explore the role of NF-kB/miR-155 and the anti-inflammatory effects of glucocorticoid treatment. RESULTS Results showed that the expression level of NF-kappaB/miR-155 was significantly elevated in the Eos CRSwNP group, accompanied by the upregulation of cytokines: tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-4, IL-5 (P<0.05) compared with the control group, the CRSsNP group or the Non-Eos CRSwNP group. The upregulation of NF-kappaB/miR-155 increased inflammatory mediator cyclooxygenase2 (COX2) while decreasing anti-inflammatory mediator Src homology-2 domain-containing inositol 5-phosphatase 1 (SOCS1), which resulted in the aberrant expression pattern of cytokines in the mice model. DEX treatment inhibited the expression of cytokines and decreased the relapse rate of Eos CRSwNP via inhibiting NF-kappaB/miR-155 (P<0.05). CONCLUSIONS The upregulation of NF-kappaB/miR-155 was crucial in mediating the aberrant expression of inflammatory cytokines in Eos CRSwNP. This molecular mechanism is a concern with the high relapse rate of Eos CRSwNP. However, glucocorticoid treatment inhibited the relapse of CRSwNP via downregulation of NF-kappaB/miR-155.

Ultrastiff metamaterials generated through a multilayer strategy and topology optimization.

Metamaterials composed of different geometrical primitives have different properties. Corresponding to the fundamental geometrical forms of line, plane, and surface, beam-, plate-, and shell-based lattice metamaterials enjoy many advantages in many aspects, respectively. To fully exploit the advantages of each structural archetype, we propose a multilayer strategy and topology optimization technique to design lattice metamaterial in this study. Under the frame of the multilayer strategy, the design space is enlarged and diversified, and the design freedom is increased. Topology optimization is applied to explore better designs in the larger and diverse design space. Beam-plate-shell-combined metamaterials automatically emerge from the optimization to achieve ultrahigh stiffness. Benefiting from high stiffness, energy absorption performances of optimized results also demonstrate substantial improvements under large geometrical deformation. The multilayer strategy and topology optimization can also bring a series of tunable dimensions for lattice design, which helps achieve desired mechanical properties, such as isotropic elasticity and functionally grading material property, and superior performances in acoustic tuning, electrostatic shielding, and fluid field tuning. We envision that a broad array of synthetic and composite metamaterials with unprecedented performance can be designed with the multilayer strategy and topology optimization.

Comprehensive DNA Methylation Analysis of Human Neuroblastoma Cells Treated With Haloperidol and Risperidone.

Accumulating evidence suggests that the epigenetic alterations induced by antipsychotics contribute to the therapeutic efficacy. However, global and site-specific epigenetic changes by antipsychotics and those shared by different classes of antipsychotics remain poorly understood. We conducted a comprehensive DNA methylation analysis of human neuroblastoma cells cultured with antipsychotics. The cells were cultured with low and high concentrations of haloperidol or risperidone for 8 days. DNA methylation assay was performed with the Illumina HumanMethylation450 BeadChip. We found that both haloperidol and risperidone tended to cause hypermethylation changes and showed similar DNA methylation changes closely related to neuronal functions. A total of 294 differentially methylated probes (DMPs), including 197 hypermethylated and 97 hypomethylated DMPs, were identified with both haloperidol and risperidone treatment. Gene ontology analysis of the hypermethylated probe-associated genes showed enrichment of genes related to the regulation of neurotransmitter receptor activity and lipoprotein lipase activity. Pathway analysis identified that among the DMP-associated genes, SHANK1 and SHANK2 were the major genes in the neuropsychiatric disorder-related pathways. Our data would be valuable for understanding the mechanisms of action of antipsychotics from an epigenetic viewpoint.

BDNF Gene's Role in Schizophrenia: From Risk Allele to Methylation Implications.

Background: Schizophrenia (SZ) is a severe chronic mental disorder with complex genetic mechanisms. Brain-derived neurotrophic factor (BDNF) is one of promising candidate genes for SZ, and rs6265 is a non-synonymous single nucleotide polymorphism (SNP) in BDNF. Methods: In this study, we performed a case-control association study of rs6265 in a cohort of Han Chinese population from eastern China, including 1,407 SZ patients and 1,136 healthy controls; and carried out a cis-mQTL (Methylation Quantitative Trait Loci) analysis for BDNF rs6265. Results: We found a positive association of rs6265 with SZ (P = 0.037), with the minor allele (A) of rs6265 conferring a protecting effect for SZ (OR = 0.89). Furthermore, cis-mQTL analysis indicates that rs6265 is associated with several methylation loci surrounding BDNF. Conclusions: Together, our findings provide further evidence to support the involvement of BDNF gene in the genesis of SZ.

The molecular structure, spectroscopic features and electronic properties of tioxolone under the external electric field.

It is very helpful to understand the properties of molecules by studying a series of physical and chemical changes in molecules under an external electric field (EEF). Tioxolone is an important bioactive compound for its wide applications in the medical field. In this work, density function theory calculations combined with EEF were used to investigate the structure, spectra and electronic properties of tioxolone. The calculated results indicate that the bond lengths, bond angles, total energy, dipole moment, charge and aromaticity of tioxolone change under EEF. As EEF increases, the energy gap of tioxolone gradually reduces and makes it easier to participate in chemical reactions. Under the effect of EEF, the infrared and UV-Vis spectra show vibrational stark effect, which causes a redshift or blueshift of the frequency. These results help to understand the effect of EEF on structures and electronic properties for tioxolone, which will further provide effective guidance for the various application of tioxolone.

Superhydrophilic and Oleophobic Porous Architectures Based on Basalt Fibers as Oil-Repellent Photothermal Materials for Solar Steam Generation.

The construction of efficient solar steam generation systems is of great importance for a range of purposes, such as desalination, distillation, and sterilization. In this study, superhydrophilic and oleophobic porous architectures are prepared by carbonization of a mixture of basalt fibers and tissue paper (BFT) followed by an oleophobic modification (O-BFT) to form oil-repellent photothermal materials for efficient solar steam generation. The as-prepared O-BFT shows high porosity, superior light absorption, and good thermal insulation (thermal conductivity=0.371 Wm-1 K-1 ). Correspondingly, a high solar energy conversion efficiency of 90 % is achieved with 1 sun irradiation. Its strong oleophobic wettability endows it with excellent oil-repellent ability. Therefore, a high energy conversion efficiency of 81 % in oily water was obtained with 1 sun irradiation, whereas the unmodified BFT only shows a low energy conversion efficiency of 26 % because of severe oil contamination, which significantly blocks water evaporation. These unique features of O-BFT makes enable efficient solar steam generation even in oily wastewater, showing great advantages over reported photothermal materials that display poor antifouling performance, which in turn largely extends its application range for practical solar steam generation.

Chirality discrimination at the carvone air/liquid interfaces detected by heterodyne-detected sum frequency generation.

The chiral signal of the carvone air/liquid interface is probed by heterodyne-detected sum frequency generation (HD-SFG) without the electronic resonance. The chiral SFG spectra exhibit two distinguishable spectral signatures. Four chiral vibrational peaks of the R- and S-carvone molecules are with opposite signs, which can directly determine the surface molecular chirality. Two achiral vibrational peaks are also observed with the same sign. The different spectral signatures can provide a detailed chirality characterization at the molecular interface.