Interventional strategies for ischemic stroke based on the modulation of the gut microbiota.

The microbiota-gut-brain axis connects the brain and the gut in a bidirectional manner. The organism's homeostasis is disrupted during an ischemic stroke (IS). Cerebral ischemia affects the intestinal flora and microbiota metabolites. Microbiome dysbiosis, on the other hand, exacerbates the severity of IS outcomes by inducing systemic inflammation. Some studies have recently provided novel insights into the pathogenesis, efficacy, prognosis, and treatment-related adverse events of the gut microbiome in IS. In this review, we discussed the view that the gut microbiome is of clinical value in personalized therapeutic regimens for IS. Based on recent non-clinical and clinical studies on stroke, we discussed new therapeutic strategies that might be developed by modulating gut bacterial flora. These strategies include dietary intervention, fecal microbiota transplantation, probiotics, antibiotics, traditional Chinese medication, and gut-derived stem cell transplantation. Although the gut microbiota-targeted intervention is optimistic, some issues need to be addressed before clinical translation. These issues include a deeper understanding of the potential underlying mechanisms, conducting larger longitudinal cohort studies on the gut microbiome and host responses with multiple layers of data, developing standardized protocols for conducting and reporting clinical analyses, and performing a clinical assessment of multiple large-scale IS cohorts. In this review, we presented certain opportunities and challenges that might be considered for developing effective strategies by manipulating the gut microbiome to improve the treatment and prevention of ischemic stroke.

N-Iodosuccinimide-Mediated Synthesis of Benzo-Fused Bisimidazoles Enabled by a One-Pot Tandem Reaction of Fluorinated Propargyl Amidines.

A N-iodosuccinimide (NIS)-mediated divergent and efficient tandem reaction between fluorinated propargyl amidines and aromatic o-diamines without any metal catalyst and additive under mild reaction conditions was developed for the synthesis of benzo-fused bisimidazoles in moderate to excellent yields. Preliminary mechanistic studies suggested that this reaction proceeded by an intermediate of secondary amine derived from 5-iodomethyl imidazole, and NIS played another role of oxidation reagent to promote the formation of a benzimidazole motif.

Comparative analysis and structure identification of oxidative metabolites and hydrogenation metabolite enantiomers for 2-fluorodeschloroketamine.

In this study, we used solid-phase extraction (SPE) with liquid chromatography-ion trap/time-of-flight mass spectrometry (LC-IT/TOF-MS) to analyze 2-fluorodeschloroketamine (2-FDCK) metabolites in human urine. The complete set of oxidative metabolites was identified, with 17 compounds divided into four groups. Furthermore, we examined the hydroxy substitution site after oxidative metabolism with theoretical calculation and 2-FDCK NMR data. We clarified the correlation of the oxidative metabolic sites with the electron cloud density in the structure. Additionally, two enantiomers of dihydro-2-fluorodeschloroketamine (dihydro-2-FDCK) were determined by a lab-made dihydro-2-FDCK hydrochloride reference substance. Their configurations were determined via nuclear magnetic resonance (NMR) spectrometry data prediction of the ACD Labs-Structure Elucidator Suite software and theoretical calculation. Moreover, the stereoselectivity of the related enzymes in hydrogenation metabolism in vivo was clarified. These findings provide an important reference for analyzing other oxidative metabolites, laying the foundation for future analysis, prediction, elucidation, and identification of the latest ketamine-type NPS metabolites.

Integrated microRNA and secretome analysis of human endometrial organoids reveal the miR-3194-5p/Aquaporin/S100A9 module in regulating trophoblast functions.

Successful placentation requires delicate communication between the endometrium and trophoblasts. The invasion and integration of trophoblasts into the endometrium during early pregnancy is crucial to placentation. Dysregulation of these functions is associated with various pregnancy complications, such as miscarriage and preeclampsia. The endometrial microenvironment has an important influence on trophoblast cell functions. The precise effect of the endometrial gland secretome on trophoblast functions remains uncertain. We hypothesized that the hormonal environment regulates the miRNA profile and secretome of the human endometrial gland, which subsequently modulates trophoblast functions during early pregnancy. Human endometrial tissues were obtained from endometrial biopsies with written consent. Endometrial organoids were established in matrix gel under defined culture conditions. They were treated with hormones mimicking the environment of the proliferative phase (Estrogen, E2), secretory phase (E2+Progesterone, P4), and early pregnancy (E2+P4+Human Chorionic Gonadotropin, hCG). miRNA-seq was performed on the treated organoids. Organoid secretions were also collected for mass spectrometric analysis. The viability and invasion/migration of the trophoblasts after treatment with the organoid secretome were determined by cytotoxicity assay and transwell assay, respectively. Endometrial organoids with the ability to respond to sex steroid hormones were successfully developed from human endometrial glands. By establishing the first secretome profiles and miRNA atlas of these endometrial organoids to the hormonal changes followed by trophoblast functional assays, we demonstrated that sex steroid hormones modulate aquaporin (AQP)1/9 and S100A9 secretions through miR-3194 activation in endometrial epithelial cells, which in turn enhanced trophoblast migration and invasion during early pregnancy. By using a human endometrial organoid model, we demonstrated for the first time that the hormonal regulation of the endometrial gland secretome is crucial to regulating the functions of human trophoblasts during early pregnancy. The study provides the basis for understanding the regulation of early placental development in humans.

Bioaugmentation on humification during co-composting of corn straw and biogas slurry.

In order to increase the nutrients and humic acid (HA) contents of corn straw (CS) derived organic fertilizer and recover resources from biogas slurry (BS) simultaneously, the co-composting of CS and BS was carried out with the addition of biochar and microbial agents including lignocellulose degrading and ammonia assimilating bacteria. The results showed that 1 kg straw could treat 2.5 L BS by recovering nutrients and bio-heat introduced evaporation. The bioaugmentation strengthened both the polyphenol and Maillard humification pathways by promoting the polycondensation of precursors (reducing sugars, polyphenols, and amino acids). HA obtained in the microbial-enhanced group (20.83 g/kg), biochar-enhanced group (19.34 g/kg), and combined-enhanced group (21.66 g/kg) were significantly higher than that in the control group (16.26 g/kg). The bioaugmentation achieved directional humification and reduced the loss of C and N by promoting the CN formation of HA. The humified co-compost had nutrient slow-release effect in agricultural production.

Placenta exosomal miRNA-30d-5p facilitates decidual macrophage polarization by targeting HDAC9.

Pregnancy involves a wide range of adaptations in the maternal body. Maternal immune tolerance towards the foreign fetus is critical for a successful pregnancy. Decidual macrophages are the primary antigen-presenting and phagocytic cells responsible for antigen presentation and apoptotic cell removal. Their phenotype changes dynamically during pregnancy. Placenta-derived exosomes (pEXO) are small vesicles carrying active biological molecules such as miRNAs, proteins, and lipids. The pEXO have been implicated in endothelial cell activation, smooth muscle cell migration, and T cell apoptosis, but it is unknown whether pEXO would affect the development and functions of decidual macrophages. In this study, we reported that pEXO stimulated macrophage polarization into alternatively activated (M2)-macrophages. Mechanistically, miRNA-30d-5p from the pEXO induced macrophage polarization to M2 phenotype by targeting histone deacetylase 9 (HDAC9). Furthermore, the conditioned medium of pEXO-treated macrophages promoted trophoblast migration and invasion. By contrast, the conditioned medium impaired the ability of endothelial cell tube formation and migration. pEXO-treated macrophages had no impact on T cell proliferation. Together, we demonstrated that pEXO polarize macrophage to acquire a decidua-like macrophage phenotype to modulate trophoblast and endothelial cell functions.

High-order mode waveguide amplifier with high mode extinction ratio written in an Er3+-doped phosphate glass.

Inscription of fiber-compatible active waveguides in high-gain glass, followed by direct interconnection with few-mode fibers, is one of the most promising solutions for all-optical mode-division multiplexing. In this work, based on the femtosecond laser writing technique, we propose a general fabrication scheme for inscribing high-order mode waveguides in glass, by carefully tailoring the cross-section of the waveguides to match the mode intensity distribution via an improved multi-scan approach. Specifically, we design and fabricate two kinds of waveguides, namely, LP01-mode waveguide and LP11-mode waveguide in a highly Er3+-doped phosphate glass, enabling the insertion loss of the waveguides to be as low as 1.88 dB, and the mode extraction factor of the LP11-mode waveguide up to ∼24 dB. Importantly, we have successfully achieved optical amplification of the waveguides, with an on-off gain as high as 3.52 dB. This novel high-order mode waveguide amplifier has broad application prospects in monolithic on-chip integrated photonic light sources and optical interconnection with few-mode fiber and/or silicon-based waveguide.

Fabrication of Super-Sized Metal Inorganic-Organic Hybrid Glass with Supramolecular Network via Crystallization-Suppressing Approach.

Metal coordination compound (MCC) glasses [e.g., metal-organic framework (MOF) glass, coordination polymer glass, and metal inorganic-organic complex (MIOC) glass] are emerging members of the hybrid glass family. So far, a limited number of crystalline MCCs can be converted into glasses by melt-quenching. Here, we report a universal wet-chemistry method, by which the super-sized supramolecular MIOC glasses can be synthesized from non-meltable MOFs. Alcohol and acid were used as agents to inhibit crystallization. The MIOC glasses demonstrate unique features including high transparency, shaping capability, and anisotropic network. Directional photoluminescence with a large polarization ratio (≈47 %) was observed from samples doped with organic dyes. This crystallization-suppressing approach enables fabrication of super-sized MCC glasses, which cannot be achieved by conventional vitrification methods, and thus allows for exploring new MCC glasses possessing photonic functionalities.

MIR497HG-Derived miR-195 and miR-497 Mediate Tamoxifen Resistance via PI3K/AKT Signaling in Breast Cancer.

Tamoxifen is commonly used for the treatment of patients with estrogen receptor-positive (ER+) breast cancer, but the acquired resistance to tamoxifen presents a critical challenge of breast cancer therapeutics. Recently, long noncoding RNA MIR497HG and its embedded miR-497 and miR-195 are proved to play significant roles in many types of human cancers, but their roles in tamoxifen-resistant breast cancer remain unknown. The results indicate that MIR497HG deficiency induces breast cancer progression and tamoxifen resistance by inducing downregulation of miR-497/195. miR-497/195 coordinately represses five positive PI3K-AKT regulators (MAP2K1, AKT3, BCL2, RAF1, and CCND1), resulting in inhibition of PI3K-AKT signaling, and PI3K-AKT inhibition in tamoxifen-resistant cells restored tamoxifen responsiveness. Furthermore, ER α binds the MIR497HG promoter to activate its transcription in an estrogen-dependent manner. ZEB1 interacts with HDAC1/2 and DNMT3B at the MIR497HG promoter, resulting in promoter hypermethylation and histone deacetylation. The findings reveal that ZEB1-induced MIR497HG depletion contributes to breast cancer progression and tamoxifen resistance through PI3K-AKT signaling. MIR497HG can be used as a biomarker for predicting tamoxifen sensitivity in patients with ER+ breast cancer.

Electrical transport properties of TiO2/MAPbI3 and SnO2/MAPbI3 heterojunction interfaces under high pressure.

The electrical transport properties of SnO2(TiO2)/MAPbI3 (MA = CH3NH3 +) heterojunction interfaces are investigated from ambient pressure to 20 GPa, and the transport properties are calculated by physical parameters such as trap energy density, binding energy, and charge transfer driving force and defect. Based on the partial density of states (PDOS) of the SnO2/MAPbI3 heterojunction interface MAI-termination and PbI2-termination, greater charge transfer driving force and higher binding energy are observed, obviously showing the SnO2-based heterojunction is more stable. The SnO2/MAPbI3 heterojunction interface possesses stronger electrical transport ability and is less prone to capture electrons compared with the TiO2/MAPbI3 heterojunction interface. The differential charge density spectrum shows that the density is lower in the trap energy level of SnO2/MAPbI3, whilst the effect of the charge transfer defect is weaker owing to the trap energy level only existing in SnO2. The SnO2/MAPbI3 heterostructure interface is less prone to capture electrons. The greater electron concentration difference is attributed to oxygen vacancy (Vo0) in the SnO-like environment, resulting in superior electron transport ability compared with the TiO-like environment.

Transition metal-doped germanium oxide nanozyme with enhanced enzyme-like activity for rapid detection of pesticide residues in water samples.

Designing highly active nanozymes for bioanalysis and environmental sensing remains a challenge. In this study, transition metal, palladium (Pd) and iron (Fe), doped germanium oxide (GeO2) nanozyme was designed and optimized. Compared with the pristine GeO2 nanozyme, the transition metal doped GeO2 nanozyme have lower Michaelis-Menten constants and higher catalytic activity, indicating that the Pd and Fe doped GeO2 nanozyme not only enhance their affinity for the substrate but also improve its catalytic activity. In addition, a colorimetric sensor based on the GeO2@Pd-H2O2-TMB system was constructed for the visual detection of simazine in water samples due to the good affinity between TMB and simazine. This sensor has good selectivity and sensitivity with a detection limit of 6.21 µM because of the highest catalytic performance of GeO2@Pd nanozyme. This study broadens the application of nanozymes in environmental field and other nanozymes can also be enhanced in activity by simple transition metal doping.

Protective Effect of Anthocyanins against Neurodegenerative Diseases through the Microbial-Intestinal-Brain Axis: A Critical Review.

With the increase in human mean age, the prevalence of neurodegenerative diseases (NDs) also rises. This negatively affects mental and physiological health. In recent years, evidence has revealed that anthocyanins could regulate the functioning of the central nervous system (CNS) through the microbiome-gut-brain axis, which provides a new perspective for treating NDs. In this review, the protective effects and mechanisms of anthocyanins against NDs are summarized, especially the interaction between anthocyanins and the intestinal microbiota, and the microbial-intestinal-brain axis system is comprehensively discussed. Moreover, anthocyanins achieve the therapeutic purpose of NDs by regulating intestinal microflora and certain metabolites (protocateic acid, vanillic acid, etc.). In particular, the inhibitory effect of tryptophan metabolism on some neurotransmitters and the induction of blood-brain barrier permeability by butyrate production has a preventive effect on NDs. Overall, it is suggested that microbial-intestinal-brain axis may be a novel mechanism for the protective effect of anthocyanins against NDs.

Bias correction for Cohen's d.

Cohen's d - a common effect size - contains a positive bias. The traditional bias correction, based on strict distribution assumption, does not always work for a small study with limited data. The non-parametric bootstrapping is not limited by distribution assumption and can be used to remove the bias in Cohen's d. A real example is included to illustrate the implementation of bootstrap bias estimation and the removal of sizable bias in Cohen's d.

Bionics design of affinity peptide inhibitors for SARS-CoV-2 RBD to block SARS-CoV-2 RBD-ACE2 interactions.

Coronavirus Disease 2019 (COVID-19), has already posed serious threats and impacts on the health of the population and the country's economy. Therefore, it is of great theoretical significance and practical application value to better understand the process of COVID-19 infection and develop effective therapeutic drugs. It is known that the receptor-binding structural domain (SARS-CoV-2 RBD) on the spike protein of the novel coronavirus directly mediates its interaction with the host receptor angiotensin-converting enzyme 2 (ACE2), and thus blocking SARS-CoV-2 RBD-ACE2 interaction is capable of inhibiting SARS-CoV-2 infection. Firstly, the interaction mechanism between SARS-CoV-2RBD-ACE2 was explored using molecular dynamics simulation (MD) coupled with molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculation method. The results of energy analysis showed that the key residues R403, R408, K417, and Y505 of SARS-CoV-2 RBD and the key residues D30, E37, D38, and Y41 of ACE2 were identified. Therefore, according to the hotspot residues of ACE2 and their distribution, a short peptide library of high-affinity SARS-CoV-2 RBD was constructed. And by using molecular docking virtual screening, six short peptides including DDFEDY, DEFEDY, DEYEDY, DFVEDY, DFHEDY, and DSFEDY with high affinity for SARS-CoV-2 RBD were identified. The results of MD simulation further confirmed that DDFEDY, DEYEDY, and DFVEDY are expected to be effective inhibitors. Finally, the allergenicity, toxicity and solubility properties of the three peptide inhibitors were validated.

Design, synthesis and in vitro biological evaluation of 2-aminopyridine derivatives as novel PI3Kδ inhibitors for hematological cancer.

Phosphoinositide-3-kinase (PI3K) involves in regulation of proliferation, cell cycle, and apoptosis, and is overexpressed in most of human malignant tumors. Therefore, the development of PI3K inhibitors has attracted great interest in tumor treatment. In this study, we designed and synthesized a series of 2-aminopyridine derivatives via a bioisosterism strategy. Among them, compound MR3278 showed superior PI3Kδ inhibitory activity (IC50 = 30 nM), as well as higher inhibitory activity to most of AML cells (e.g., MOLM-16 and Mv-4-11 cells with IC50 values of 2.6 µM and 3.7 µM, respectively) than Idelalisib. Further cell studies indicated that MR3278 could induce G2/M phase arrests and cell apoptosis of Mv-4-11 cells via PI3K dependent pathway in a dose dependent manner. In addition, in silico physicochemical and ADMET evaluation revealed its drug-like properties with satisfactory toxicity profiles. These results indicate that MR3278 can be identified as a promising new lead compound to the current PI3Kδ inhibitor and is worthy of further profiling.

Prediction of drug-induced hepatotoxicity based on histopathological whole slide images.

Liver is an important metabolic organ in human body and is sensitive to toxic chemicals or drugs. Adverse reactions caused by drug hepatotoxicity will damage the liver and hepatotoxicity is the leading cause of removal of approved drugs from the market. Therefore, it is of great significance to identify liver toxicity as early as possible in the drug development process. In this study, we developed a predictive model for drug hepatotoxicity based on histopathological whole slide images (WSI) which are the by-product of drug experiments and have received little attention. To better represent the WSIs, we constructed a graph representation for each WSI by dividing it into small patches, taking sampled patches as nodes and calculating the correlation coefficients between node features as the edges of the graph structure. Then a WSI-level graph convolutional network (GCN) was built to effectively extract the node information of the graph and predict the toxicity. In addition, we introduced a gated attention global context vector (gaGCV) to combine the global context to make node features to contain more comprehensive information. The results validated on rat liver in vivo data from the Open TG-GATES show that the use of WSI for the prediction of toxicity is feasible and effective.

In situconstruction of ZIF-67 derived Mo2C@cobalt/carbon composites toward excellent electromagnetic wave absorption properties.

Electromagnetic wave (EM) absorption materials with multi-loss mechanisms and optimized impedance matching have attracted considerable attention as a means to combat the ever-increasing electromagnetic pollution. Molybdenum carbide (Mo2C) with outstanding environmental stability and high conductivity is becoming popular as EM absorption materials. Herein, the CoMoO4@ZIF-67 precursor was synthesized by anin situsacrificial template method, followed by calcining to synthesize porous Mo2C@cobalt/carbon (Mo2C@Co/C) composites. The homogeneously dispersed Mo2C and Co nanoparticles as well as the porous structures resulted from the novelin situfabrication strategy could generate abundant interfaces and induce effective multi-loss mechanisms including polarization loss, conductivity loss, magnetic loss, and so on. The as-prepared optimal composite (Mo2C@Co/C-10) demonstrates superior electromagnetic (EM) wave absorption performance with a maximum reflection loss value of -37.9 dB at the matching thickness of 2.3 mm, and the effective absorption bandwidth (EAB) of 5.52 GHz was realized at 1.9 mm. The excellent EM wave absorption properties can be attributed to the good impedance matching, synergistic effects among different loss mechanisms, multiple reflection and scattering. This work not only developed an effective ternary EM absorption materials of Mo2C@Co/C, but also propose a facilein situstrategy to fabricate more highly- dispersed mecarbide-basedased materials.

Identification of Immune-Active Peptides in Casein Hydrolysates and Its Transport Mechanism on a Caco-2 Monolayer.

In this study, we investigated the transport mechanism of immune-active peptide fragments isolated from casein gastrointestinal hydrolysates via a Caco-2 monolayer. The casein gastrointestinal hydrolysates could stimulate B-lymphocyte proliferation and reduce the TNF-α level. Then, we identified the bioactive peptide fragments derived from casein gastrointestinal hydrolysis using LC-MS/MS. Our results demonstrated that the transport mechanism of five immune-active peptides at the cell level was bypass transport. In addition, the majority of peptide RYPLGYL was transported through the monolayer cell membrane as an intact form for playing immune-active functions. The KHPIK and FFSDK were mainly degraded into small fragments, except for a small amount passing through Caco-2 cells in an entire form. Overall, these results suggested that casein or its immune-active peptides might play a role in regulation of the intestinal immune system.

Coral Reef Arks: An In Situ Mesocosm and Toolkit for Assembling Reef Communities.

Coral reefs thrive and provide maximal ecosystem services when they support a multi-level trophic structure and grow in favorable water quality conditions that include high light levels, rapid water flow, and low nutrient levels. Poor water quality and other anthropogenic stressors have caused coral mortality in recent decades, leading to trophic downgrading and the loss of biological complexity on many reefs. Solutions to reverse the causes of trophic downgrading remain elusive, in part because efforts to restore reefs are often attempted in the same diminished conditions that caused coral mortality in the first place. Coral Arks, positively buoyant, midwater structures, are designed to provide improved water quality conditions and supportive cryptic biodiversity for translocated and naturally recruited corals to assemble healthy reef mesocosms for use as long-term research platforms. Autonomous Reef Monitoring Structures (ARMS), passive settlement devices, are used to translocate the cryptic reef biodiversity to the Coral Arks, thereby providing a "boost" to natural recruitment and contributing ecological support to the coral health. We modeled and experimentally tested two designs of Arks to evaluate the drag characteristics of the structures and assess their long-term stability in the midwater based on their response to hydrodynamic forces. We then installed two designs of Arks structures at two Caribbean reef sites and measured several water quality metrics associated with the Arks environment over time. At deployment and 6 months after, the Coral Arks displayed enhanced metrics of reef function, including higher flow, light, and dissolved oxygen, higher survival of translocated corals, and reduced sedimentation and microbialization relative to nearby seafloor sites at the same depth. This method provides researchers with an adaptable, long-term platform for building reef communities where local water quality conditions can be adjusted by altering deployment parameters such as the depth and site.