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[Display omitted] Hypothesis: Constructing a segregated network in electrically conductive polymer composites (ECPCs) is an effective method to lower the electrical percolation threshold. The segregated network structure can be formed naturally via polymerizing Pickering high internal phase emulsions (HIPEs) because solid particles are assembled at water-oil interfaces. However, most Pickering stabilizers show poor electrical conductivity. In this work, we propose a facile method to prepare lightweight ECPCs with well-controlled segregated structure via Ti 3 C 2 T x -stabilized HIPE templating. Experiments: Hydrophilic Ti 3 C 2 T x flakes are delicately hydrophobized with a double-chain cation surfactant. The morphology of Ti 3 C 2 T x flakes is investigated by transmission electron microscopy (TEM) and atom force microscopy (AFM). The surface properties of modified Ti 3 C 2 T x are characterized by zeta potential and water contact angle tests. The stability of Ti 3 C 2 T x -stabilized emulsions, and the structure of prepared ECPCs are systematically investigated. Findings: Surface modified Ti 3 C 2 T x flakes are used to stabilize water-in-oil (w/o) HIPEs for the first time. After the polymerization of continuous oil phase, ECPCs are successfully prepared with closed-cell porous structure. The pore size and size distribution of porous composites can be tailored by varying the content of Ti 3 C 2 T x flakes. The Ti 3 C 2 T x flakes are mainly immobilized at the water–oil interface and eventually form the segregated network in composites. Combining the unique segregated network and the outstanding metallic conductivity of Ti 3 C 2 T x , the prepared porous polymer composites exhibit good conductivity even with ultralow Ti 3 C 2 T x content of 0.016 vol%. [ABSTRACT FROM AUTHOR]

[Display omitted] Janus nanosheets, which have two surfaces of different functionalities, exhibit unique interfacial properties. In this work, we propose a facile and scalable technique for preparation of silica-based Janus nanosheets, which is based on formation of high internal phase water-in-oil emulsions stabilized solely by alkyl-substituted polyethoxysiloxanes due to their hydrolysis-induced interfacial activity. Janus nanosheets are then obtained by crushing the silica foams converted from such emulsions. The morphology of Janus nanosheets is investigated by field-emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM). The chemical structure of functional silica materials is characterized by Fourier transform infrared spectroscopy (FT-IR). The asymmetric structure of silica nanosheets is observed by confocal laser scanning microscopy. The resulting nanosheets have a rough hydrophobic surface and a smooth hydrophilic one, and are capable of stabilizing Pickering oil-in-water emulsions. Remarkably, pH-responsiveness of emulsions can be attained using the nanosheets whose hydrophilic surface is substituted with amino groups. Fast oil–water separation is achieved by the Janus nanosheets, which has been demonstrated by the nanosheets with a polystyrene-coated hydrophobic surface. This work paves a new avenue for large-scale production of functional silica-based Janus nanosheets suitable for numerous promising applications. [ABSTRACT FROM AUTHOR]

[Display omitted] The development of stable and efficient heterojunction photocatalysts for wastewater environmental purification exhibits a significant challenge. Herien, a promising binary heterojunction complex comprising boron subphthalocyanine bromide/bismuth oxychloride (SubPc-Br/BiOCl) was successfully synthesized using the hydrothermal method, which involved the self-assembled of SubPc-Br on the surface of BiOCl via intermolecular π-π stacking interactions to compose an electron-transporting layer. The photocatalytic efficiency of SubPc-Br/BiOCl for the degradation of tetracycline and the minocycline exhibited a substantial improvement of 29.14% and 53.72%, respectively, compared to the original BiOCl. Experimental characterization and theoretical calculations elucidated that the enhanced photocatalytic performance of the SubPc-Br/BiOCl composite photocatalysts stemmed from the S-scheme electron transport mechanism at the interface between BiOCl and SubPc-Br supramolecules, which broadened the visible light absorption range, increased the carrier molecular efficiency, and accelerated the carriers. Furthermore, molecular dynamic (MD) simulations provided insights into the action trajectories of the two semiconductors, revealing that the presence of SubPc-Br enhances the water and organic pollutant adsorption capabilities of the BiOCl surface within the supramolecular array system. In conclusion, the synthesis and analysis of the binary heterojunction complex SubPc-Br/BiOCl yield valuable insights into the efficient photocatalytic degradation of antibiotics, holding great promise for diverse environmental applications. [ABSTRACT FROM AUTHOR]

Effective treatment of sewage by wastewater treatment plants (WWTPs) are essential to protecting water environment as well as people's health worldwide. However, operation of WWTPs is usually intricate due to precarious influent characteristics and nonlinear sewage treatment processes. Effective modeling of WWTPs can provide valuable decision-making support to facilitate their daily operations and management. In this study, we have built a novel hybrid model by combining a process-based WWTP model (GPS-X) with a data-driven machine learning model (Random Forest) to improve the simulation of long-term hourly effluent ammonium-nitrogen concentration of a WWTP. Our study results have shown that the hybrid GPS-X-RF model performs the best with a coefficient of determination (R2) of 0.95 and root mean squared error (RMSE) of 0.23 mg/L, followed by the GPS-X model with a R2 of 0.93 and RMSE of 0.33 mg/L and last the Random Forest model with a R2 of 0.84 and RMSE of 0.41 mg/L. Capable of incorporating wastewater treatment mechanisms and utilizing superior data mining capabilities of machine learning, the hybrid model adapts better to the large fluctuations in influent and operating conditions of the WWTP. The proposed hybrid modeling framework may be easily extended to WWTPs of various size and types to simulate their operations under increasingly variable environmental and operating conditions. • Hourly WWTP influent flow and pollutant content fluctuate enormously over 2 years. • GPS-X tends to overestimate high effluent NH 4 +-N observations throughout simulation. • RF tends to underestimate high effluent NH 4 +-N observations while overestimating low ones. • The hybrid GPS-X-RF model outperforms both the stand-alone GPS-X and RF model. [ABSTRACT FROM AUTHOR]

This paper describes numerical and laboratory investigations that have been carried out to gain a better understanding of the physical processes involved in offshore breaking wave impacts on a large offshore structure. The findings are relevant to offshore and coastal structures and to identifying the extreme loads, peak pressures and maximum run-up needed for their design. A truncated wall in a wave flume is used to represent a vertical section of an FPSO (Floating Production Storage and Offloading) hull, which is a typical large offshore structure. Four types of wave impact were identified in the tests, and are referred to as slightly-breaking, flip-through, large air pocket and broken wave impacts. Physical modelling was undertaken in Plymouth University’s COAST Laboratory and the open source Computational Fluid Dynamics (CFD) package-Open Field Operation and Manipulation (OpenFOAM) was adopted to study focused wave generation and wave impact on the hull. The method solves incompressible Unsteady Reynolds-averaged Navier–Stokes Equations (URANSE) using a finite volume method with two phase flows. A Volume of Fluid (VoF) interface capturing approach is used to model the free surface. A NewWave boundary condition is used to generate focused wave groups based on the first plus second-order (hereafter second-order) Stokes wave theory in the Numerical Wave Tank (NWT). By changing the focus location with respect to the wall, the wave impact type was altered in both the numerical and laboratory investigations. The results show that for the four wave impact types tested good agreement was achieved between numerical predictions and experimental measurements of surface elevation, run up and impact force. The peak pressures predicted by the simulation are lower than the experimentally measured results due to time step constraints, although the shape of the pressure time history is very similar. Four distinct wave impact types are identified for the vertical hull section and are found to be similar in character to those observed for a full depth vertical wall. The predicted force on the hull is found to be greatest for the large air pocket impact, and the highest run-up for the slightly-breaking wave impact. The pressure records show a high degree of spatial and temporal variation though the highest pressure recorded at any location was due to flip-through. This research has shown that different characteristic wave impact types are responsible for maximum load and greatest wave run-up and so need to be considered separately for design purposes. [ABSTRACT FROM AUTHOR]

Highlights: [•] Polystyrene microspheres with string-like structure. [•] Polymer microspheres are stabilized by one-dimensional network. [•] The effects of pH value and ion strength on the morphology. [Copyright &y& Elsevier]

Chimeric antigen receptor T cell (CAR-T) therapy is a late-model of immune cell therapy that has been shown to be effective in refractory/recurrent B-cell leukemia and lymphoma. Compared with the traditional anti-tumor methods, CAR-T cell therapy has the advantages of higher specificity, stronger lethality and longer-lasting efficacy. Although CAR-T cells have made significant progress in the treatment of hematologic malignancies, diverse difficulties remain in the treatment of solid tumors, including immune escape due to tumor antigen heterogeneity, preventing entry or limiting the persistence of CAR-T cells by physical or cytokine barriers and along with other immunosuppressive molecule and cells in the tumor microenvironment (TME). Otherwise, the intracellular signaling of CAR also impact on CAR-T cells persistence. Appropriate modification of intracellular costimulatory molecular signal in the structure of CAR or coexpression of CAR and cytokines can provide a way to enhance CAR-T cells activity. Additionally, CAR-T cells dysfunction due to T cell exhaustion is associated with multi-factors, especially transcription factors, such as c-Jun, NR4A. Engineering CAR-T cells to coexpress or knockout transcription factors in favor of T CM memory CAR-T cells differentiation was proved to prolonged the survival of CAR-T cells. Finally, combination of CAR-T cells with oncolytic viruses, nanoparticles or immune checkpoint inhibitors provides an effective measure to improve CAR-T cells function. Here, we discuss all of these advances and challenges and review promising strategies for treating solid tumors. In particular, we also highlight that CAR-T cells have enormous potential to be used in combination with other immunotherapies. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Exfoliated graphene oxide (GO) nanosheets with hydrophilic oxygen-containing functional groups and hydrophobic residual conjugated structure are prepared by the oxidation of graphite powders. Polymerization of styrene stabilized by GO nanosheets is conducted at varied pH values. The morphology of the products is observed by field-emission scanning electron microscope (FE-SEM). It is found that GO coated polystyrene (PS) microspheres with narrow size distribution are obtained, although highly hydrophilic GO nanosheets cannot stabilize the monomer droplets in aqueous phase. Flocculation of polymer microspheres and GO nanosheets embedded in the PS matrix is induced by further decreasing the hydrophilicity of stabilizer. FT-IR, UV–vis spectra, XRD patterns and TGA results indicate the strong interaction between resulted PS chains and GO nanosheets during the initial stage of the polymerization. The amphiphilicity of GO nanosheets and the interaction between polymer and stabilizer are considered to be responsible for the fabrication of GO coated PS colloidal particles. [Copyright &y& Elsevier]

Abstract: Slightly surface-functionalized polystyrene (PS) microspheres are prepared by photocatalytic Pickering emulsion polymerization using sodium styrene sulfonate (SSS)-modified titania hydrosol as a stabilizer. Aqueous electrophoresis measurements indicate the adsorption of bifunctional SSS anions on the surface of titania nanoparticles via electrostatic interaction. SSS molecules participate in the copolymerization with the monomers before the nucleation and thus have a great effect on the morphology and surface structure of the obtained PS microspheres. Appropriate SSS concentration leads to PS microspheres with small size, narrow distribution, and uniform surface chemistry. This kind of polymer particles can be used as a good candidate for the electrophoretic displays because of their high colloidal stability and electrophoretic mobility in the apolar solvent. [Copyright &y& Elsevier]

Recently, the pollution of microplastics (MPs) in the global freshwater environment has become increasingly problematic, but there are few studies on the freshwater environment risks of MPs. The present study, therefore, has investigated the single and combined effects of MPs and lead (Pb) on the freshwater algal Microcystis aeruginosa. Results showed that Pb-only (>0.05 mg·L−1) promoted the growth of algal cells, while MPs-only (1 mg L−1) resulted in growth inhibition. However, compared with the corresponding concentration of Pb-only groups, the growth of algal cells was promoted in MPs + Pb treatments. MPs-only and Pb-only (0.5 mg L−1) both reduced the content of photosynthetic pigments and affected algal photosynthesis. The MPs-only treatment and MPs + Pb2+ (no pretreatment, 0.5 mg L−1 Pb2+) treatments showed significant cell aggregation. At the same time, MPs-only caused a significant increase in bound extracellular polysaccharides (bEPS), while 0.5 mg L−1 Pb reduced bEPS. Furthermore, under high Pb stress (0.5 mg L−1), the effects of combined MPs and Pb on chlorophyll content, antioxidant enzyme activity (peroxidase (POD), catalase (CAT)), and damage to algal cells were less compared to individual effects, and the combination of MPs and Pb had a synergistic effect on promoting aggregations of M. aeruginosa. These results demonstrate that single and combined effects of MPs and Pb can induce differential responses in the freshwater algal M. aeruginosa , which can have a significant impact on aquatic ecosystems. • MPs and Pb have a synergistic effect on promoting the growth of Microcystis aeruginosa. • The MPs-only treatment and MPs + Pb (no pretreatment, 0.5 mg L-1 Pb) treatment showed significant cell aggregation. • The effects of combined MPs and Pb (0.5 mg L-1) on chlorophyll content, CAT and POD activity were less than individual effects. [ABSTRACT FROM AUTHOR]

The study investigated the responses of the submerged macrophyte Vallisneria natans (V. natans) to snails (Bellamya aeruginosa) at different densities, with changes in physiological parameters, morphology, leaf-epiphytic bacteria community and water quality parameters examined. The changes of water quality parameters (pH, total nitrogen (TN), total phosphorus (TP) and total organic carbon (TOC)) indicated that snails secreted nutrients into water. Changes in morphological and physiological parameters (fresh weight, root length, shoot height, chlorophyll, malondialdehyde (MDA), activities of superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD)) demonstrated that the presence of snails were beneficial to the growth of submerged macrophytes. Microbial diversity analyses indicated that snails could decrease microbial community richness and diversity. At medium densities (340 ind. m−2), an increase in snail density was beneficial to the growth of submerged macrophytes. The results of this study provide theoretical guidance and technical support for the maintenance and restoration of submerged macrophytes. Image 1 • Vallisneria natans responses to snails were studied. • Snails at 340 ind. m−2 were beneficial to the growth of Vallisneria natans. • Snails could decrease microbial community richness and diversity of leaf biofilms. [ABSTRACT FROM AUTHOR]

The integrated effects of water flow on submerged macrophytes (Vallisneria natans) and leaf biofilms were comprehensively investigated in eutrophic microcosm. Changes in aquatic environmental factors were analyzed and water flow was found to elevate eutrophic water quality, especially in terms of TP removal. The removal efficiency of TP reached 78.95% in flowing water, which was more than 10-fold higher than in static water. Water flow altered the morphological and physiological characteristics of plants, decreasing the cell wall thickness and rate of photosynthesis, while promoting the accumulation of soluble sugar and protein in leaves. The starch content also increased with water flow, and significantly larger starch granules were observed in chloroplast. Furthermore, oxidative damage was evidenced by the consistently higher content of malondialdehyde in flowing water. Superoxide dismutase (SOD), peroxidase (POD) and Catalase (CAT) were induced in plants exposed to water flow, as an antioxidant stress response. The results of 16S rRNA high-throughput sequencing analysis showed that the structure of the biofilm microbial community changed in response to water flow. These results expand our understanding of the effects of water flow on submerged macrophytes and periphyton biofilms in eutrophic environments. • Water flow could help to improve water quality in eutrophic environments. • Plant morphological and physiological parameters were altered by water movement. • Larger starch granules were observed in chloroplasts exposed to flowing water. • The biofilm microbial community structure changed in response to water flow. [ABSTRACT FROM AUTHOR]

Eastern China is a typical region that suffers from harmful cyanobacterial blooms. Numerous studies have focused on bloom formation mechanisms; however, the detailed mechanisms remained unclear. Our study explored the influence of four metal ions (Ca, Cu, Pb and Cd) on Microcystis aeruginosa to determine their effects on bloom formation. We found that Ca concentrations higher than 100 mg L−1 contributed to cyanobacterial bloom formation. The presence of Ca triggered the anti-oxidation process and promoted the secretion of extracellular polysaccharides, thus inducing aggregation of algal cells and enhancing their buoyancy 2.1-fold more than the control (p ＜0.05). The reverse regulation of dissolved CO 2 to bicarbonate by carbonic anhydrase formed a large amount of carbonate and decreased the growth rate by 38–56%. Cu (>0.1 mg L−1) presented significant toxicity to algal cells while Pb (>1 mg L−1) suppressed the algal growth rate due to the acidic condition. Cd (<0.1 mg L−1) exhibited no apparent toxicity to the algae. Furthermore, as the buoyancy increased, Cd was likely to facilitate the formation of cyanobacterial blooms, which needs further research. These findings can provide a theoretical basis for eutrophic lake management and contribute to the development of water quality and wastewater discharge standards. • The buoyancy of algal cell increased with increasing cell aggregation proportion. • Four metal ions stimulate SOD, POD, CA and MDA in M. aeruginosa. • The regulation of CA in algal cells promoted the precipitation with metal ions. • Calcium higher than 100 mg L−1 was beneficial for bloom formation. [ABSTRACT FROM AUTHOR]

Monolithic wood carbon armed with mesoporous nickel-silica nanocomposite layer is a stiff and highly efficient catalyst for toluene steam reforming. [Display omitted] • A thin Ni-silica layer was in-situ grown on the wall of wood carbon channels. • Small Ni nanoparticles are embedded in mesoporous silica with carbon protection. • The hardness and hydrothermal stability of monolithic wood carbon was improved. • The multilevel pore structure enhances mass transfer and avoids coke deposition. • The monolithic catalyst exhibits excellent tar steam reforming performance. Steam reforming is an effective measure for biomass tar elimination as well as H 2 -rich syngas (H 2 + CO) production. However, the granular or powdery Ni-based catalysts are prone to deactivation, which is caused by inappropriate mass transfer and clogging of catalyst bed. Herein, monolithic wood carbon (WC) with low-tortuosity microchannels is armed with a carbon-coated mesoporous nickel-silica nanocomposite (Ni-SiO 2 @C) layer via an evaporation-induced self-assembly and calcination procedure for toluene (tar model compound) steam reforming. The quality of the Ni-SiO 2 @C layer growing on the surface of WC microchannel is affected by the molar ratios of Si/Ni feed. A uniform thin-layer coverage is obtained on the Ni-15SiO 2 @C/WC (Si/Ni = 15) catalyst, where highly dispersed Ni nanoparticles (average size of 6.6 nm) with appropriate metal-support interaction and remarkable mechanical strength are achieved. The mass transfer, coke resistance, and hydrothermal stability of the Ni-15SiO 2 @C/WC catalyst were significantly improved by the multilevel structure assembled from the WC microchannels and the secondary ordered SiO 2 mesopores. A stable toluene conversion over 97% with an H 2 yield of 135 μmol/min was obtained at 600 °C on the Ni-15SiO 2 @C/WC catalyst. This work opens a new window for facilely constructing high-performance wood carbon-based monolithic tar reforming catalyst. [ABSTRACT FROM AUTHOR]

• 6-Gingerol attenuates pyroptosis in septic mice. • 6-Gingerol inhibits macrophage pyroptosis and release of inflammatory cytokines. • 6-Gingerol attenuates macrophage pyroptosis by blocking MAPK activation. • ERK agonist produced the opposite effects. Sepsis is a major cause of death for ICU patients. Sepsis development depends heavily on the presence of mature IL-1β cytokine. This study evaluates the potential therapeutic properties of a bioactive compound known as 6-gingerol on sepsis. This compound has previously been demonstrated to possess anti-inflammatory properties both in vivo and in vitro. C57BL/6 mice was used to establish models of sepsis by means of cecal ligation and puncture (CLP). Upon treatment with 6-gingerol, we assessed the survival rate of mice and measured the levels of key pro-inflammatory cytokines in serum and colon tissues. Sepsis pathogenesis was further explored using the RAW264.7 cell line and bone marrow-derived macrophages (BMDMs) treated with ATP and lipopolysaccharide (LPS). The impact of 6-gingerol on pyroptosis was also examined. In addition, we assessed the role of MAPK signaling in 6-gingerol-induced effects in BMDMs and RAW264.7 cells. In CLP mice, 6-gingerol significantly ameliorated sepsis development, which was associated with the reduction of serum IL-1β. In BMDMs and RAW264.7 cells, 6-gingerol strongly attenuated pyroptosis as well as the release of caspase-1p20, HMGB1, mature IL-1β, IL-18 in response to ATP and LPS treatment. 6-Gingerol conferred these effects by blocking MAPK activation. Exposure to an ERK agonist (EGF) reversed effects of 6-gingerol, causing pyroptosis, LDH and caspase-1p20 release. By targeting MAPK signaling, 6-gingerol significantly suppressed secretion of pro-inflammatory cytokines and inhibited macrophage cells pyroptosis resulting in overall inhibition of sepsis development. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Hydrogen generation photocatalyzed by low-cost graphite carbon nitride (g-C 3 N 4) is a fascinating and effective route to solve energy crisis, but is mainly limited by the few reactive sites, low carrier separation efficiency and mediocre visible-light utilization. In this work, these limitations were tackled through a facile eco-friendly precursor pretreatment by tuning bulk g-C 3 N 4 into porous structure. This pretreatment restricted agglomeration in the subsequent condensation and created more porous channels for charge carrier transfer and more surface active sites for reaction. The modified g-C 3 N 4 has larger surface area, broader visible-light response, enhanced electron migration capacity and prolonged lifetime of photogenerated carriers. These well-amended g-C 3 N 4 nanosheets possess an average hydrogen evolution rate 5.7 times that of bulk g-C 3 N 4. This work affords a facile, eco-friendly and scalable strategy to design or synthesize other porous materials. [ABSTRACT FROM AUTHOR]

Periodontitis, a chronic infectious disease induced by microbial biofilm, is one of the most common diseases worldwide. Scaling and root planning (SRP) has always been recognized as the typical treatment. However, the therapeutic efficiency is often limited due to the intraoperative bleeding and the limitations of instruments. Non-thermal atmospheric plasma (NTP) appears to be a potential tool for periodontitis due to its promising biofilm degradation and decontamination effects. In this study, we investigated the role of NTP, as an adjuvant approach for the treatment of ligature-induced periodontitis in rats. Herein we showed that SRP or SRP-NTP application attenuated the periodontitis-induced alveolar bone loss, reflected by the increased BV/TV value and the decreased CEJ-AB distance, which might be related to the lower detection rate of periodontal pathogen in SRP and SRP-NTP groups. Besides, SRP-NTP rats showed less bone loss and lower CEJ-AB distance than that of SRP group at 30d post treatment, indicating a more comprehensive and long-lasting effect of SRP-NTP. A remarkable decrease of osteoclast number and lower expression of RANKL was also detected in SRP-NTP rats. In addition, expression of inflammatory-related cytokines such as TNF-α and IL-1β decreased significantly in SRP-NTP group, while IL-10 level increased substantially. These results together illustrated that a combination of SRP and NTP treatment was an effective way to prevent periodontitis progress, which reduced alveolar bone loss and promoted periodontium restoration in ligature-induced periodontitis rats. In conclusion, non-thermal plasma treatment may be considered as a feasible and effective supplementary approach to control periodontitis. [ABSTRACT FROM AUTHOR]

Mesoporous silica-encapsulated iron materials contribute to the suppression of self-aggregation and thereby enhances the Fischer-Tropsch synthesis activity. However, constructing Fe-based supported catalysts with high activity and selectivity in the Fischer-Tropsch synthesis to lower olefins (FTO) by a conventional mesoporous silica support has been proven challenging due to its low hydrothermal stability and low reducibility. Herein, we developed a core-shell Fe@SiO 2 -GC structure with an optimized interface of the catalyst by introducing graphitic carbon (GC) that weakened the Fe-SiO 2 interaction. Transmission electron microscopy and nitrogen adsorption-desorption characterization proved GC-modified catalysts had well-defined core-shell structures. The Fe@SiO 2 -GC-2 containing the optimal GC content had the largest surface area and pore volume, and outperformed Fe 2 O 3 @SiO 2 in terms of CO conversion (60.1%) and C 2 -C 4 olefin selectivity (40.7%) within 100 h. The significant improvement of FTO performance was attributed to the rigid porous framework of GC, which allowed free access of syngas and inhibited mesoporous channel collapse during FTO, so the catalytic activity and stability were improved by the synergism between higher Fe dispersion and reducibility. Moreover, the narrow well-defined mesoporous channel also exerted a modest spatial restriction effect, which inhibited the formation of long-chain hydrocarbon and tailored the product distribution toward lower distillate, thus improving the selectivity toward C 2 -C 4 . [ABSTRACT FROM AUTHOR]

The drug-drug interactions (DDIs) between tacrolimus and voriconazole are highly variable among individuals. We aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the DDIs in people with different CYP3A5 and CYP2C19 alleles. First, pharmacokinetic data of humans receiving tacrolimus with or without voriconazole from the literature were used to construct and validate the PBPK model. Thereafter, we developed a model incorporating the metabolism of voriconazole mediated by CYP2C19 and the inhibitory effect of voriconazole on CYP3A4/5. Finally, the model was used to evaluate the dose adjustment of tacrolimus in people with different CYP3A5 and CYP2C19 alleles. When tacrolimus was administered alone (3 mg PO, single dose), the predicted AUC 0-∞ of tacrolimus in CYP3A5 nonexpressers (19.22) was 3.5-fold higher than that in expressers (5.48). Following voriconazole (200 mg PO, bid) administration in human with different CYP2C19 genotypes, the AUC 0-∞ of tacrolimus increased by 5.1- to 8.3-fold in CYP3A5 expressers and by 5.3- to 10.2-fold in CYP3A5 nonexpressers. The lower the gene expression level of CYP2C19 in the population, the higher the exposure to tacrolimus. When tacrolimus was combined with voriconazole (200 mg, bid; 400 mg, bid, on Day 1), the final model simulations suggested that the dose regimen of tacrolimus should be regulated to 0.15 mg/kg/day (qd) in CYP3A5 expressers with different CYP2C19 genotypes. For CYP3A5 nonexpressers, the dosing schedule of tacrolimus should be modified to 0.05 mg/kg/24 h for patients with 2C19 EM, 0.05 mg/kg/48 h for 2C19 IM and 0.05 mg/kg/72 h for 2C19 PM. In conclusion, a PBPK model with CYP3A5 and CYP2C19 polymorphisms was successfully established, providing more insights regarding the DDIs between tacrolimus and voriconazole to guide the clinical use of tacrolimus. • The TAC-VOC-DDIs have an important effect on the safe and effective use of TAC. • The TAC-VOC-DDIs are highly variable in people with different CYP3A5/CYP2C19 alleles. • DDI PBPK model with CYP3A5/CYP2C19 polymorphisms was successfully established. • The dose of TAC was recommended in patients with different CYP3A5/CYP2C19 genotypes. [ABSTRACT FROM AUTHOR]

Highlights: [•] Functions of OLA1 in mammalian cells are poorly understood. [•] Downregulation of OLA1 enhances cell adhesion and spreading while overexpression of OLA1 inhibits these processes. [•] OLA1 regulates protein levels of FAK and phosphorylation of cofilin. [•] OLA1 plays a negative role in cell-matrix adhesion and spreading. [ABSTRACT FROM AUTHOR]

• Inflammatory mediators up regulated in maternal-fetal interface during labor. • Maternal-fetal interface should also include the uterine and fetal circulation. • Elevated maternal inflammatory factors could enter the fetal circulation during labor. Elevated cytokines, like IL-1βand IL-6, are known to contribute to the pathogenesis of labor. However, the change of inflammatory mediators in maternal-fetal interface to fetal circulation is obscure. Study design and methods: We investigated the changes of inflammatory cytokines, chemokines and macrophage in maternal-fetal interface tissues and fetal circulation of women in labor vs. non-labor. Human myometrium, placenta, decidua, fetal membrane and umbilical blood were obtained from in-labor and non-in-labor women who eventually delivered live, singleton infants at term (>37 weeks gestation) by elective caesarean section. Luminex was used to measure the level of cytokines (TNF-α, IL-1β, IL-6, IL-8) and chemokines (MCP-1, GM-CSF, MIP-1α, MIP-1β) in each sample (tissue and umbilical blood). Macrophage infiltration was demonstrated by immunohistochemistry. During labor, the level of cytokines TNF-α, IL-1β, IL-6 and IL-8 and chemokine MCP-1 and MIP-1β in myometrium is significantly higher (p < 0.05), than those obtained from non-laboring patients. This increase coincides with the influx of macrophage into the myometrium. In addition, IL-1β and IL-8 (p < 0.05) are also up regulated in fetal membrane during labor compared to non-labor. The cytokines do not change significantly in placenta and decidua tissue. In fetal circulation, IL-6 (p < 0.05) is up regulated in umbilical vein blood in labor group. IL-8 (p = 0.08) in umbilical vein also show an increasing trend during labor. There are markedly elevated inflammatory mediators in maternal-fetal interface during labor. The increased maternal inflammatory factors released into the fetal circulation through placenta circulation at the time of labor. This increase coincides with the influx of macrophage into the pregnancy tissue, suggesting that the inflammatory response might play an important role in the onset of labor. [ABSTRACT FROM AUTHOR]

Abstract: Performing two tasks simultaneously (dual-task) is common in human daily life. The neural correlates of dual-task processing remain unclear. In the current study, we used a dual motor and counting task with functional MRI (fMRI) to determine whether there are any areas additionally activated for dual-task performance. Moreover, we investigated the functional connectivity of these added activated areas, as well as the training effect on brain activity and connectivity. We found that the right cerebellar vermis, left lobule V of the cerebellar anterior lobe and precuneus are additionally activated for this type of dual-tasking. These cerebellar regions had functional connectivity with extensive motor- and cognitive-related regions. Dual-task training induced less activation in several areas, but increased the functional connectivity between these cerebellar regions and numbers of motor- and cognitive-related areas. Our findings demonstrate that some regions within the cerebellum can be additionally activated with dual-task performance. Their role in dual motor and cognitive task processes is likely to integrate motor and cognitive networks, and may be involved in adjusting these networks to be more efficient in order to perform dual-tasking properly. The connectivity of the precuneus differs from the cerebellar regions. A possible role of the precuneus in dual-tasks may be to monitor the operation of active brain networks. [Copyright &y& Elsevier]

Abstract: In addition to its role as a morphogen, Sonic hedgehog (Shh) has also been shown to function as a guidance factor that directly acts on the growth cones of various types of axons. However, the noncanonical signaling pathways that mediate the guidance effects of Shh protein remain poorly understood. We demonstrate that a novel signaling pathway consisting of protein kinase Cα (PKCα) and integrin-linked kinase (ILK) mediates the negative guidance effects of high concentration of Shh on retinal ganglion cell (RGC) axons. Shh rapidly increased Ca2+ level and activated PKCα and ILK in the growth cones of RGC axons. By in vitro kinase assay, PKCα was found to directly phosphorylate ILK on threonine-173 and -181. Inhibition of PKCα or expression of a mutant ILK with the PKCα phosphorylation sites mutated (ILK-DM), abolished the Shh-induced macropinocytosis, growth cone collapse and repulsive axon turning. In vivo, expression of a dominant negative PKCα or ILK-DM disrupted RGC axon pathfinding at the optic chiasm but not the projection toward the optic disk, supporting that this signaling pathway plays a specific role in Shh-mediated negative guidance effects. [Copyright &y& Elsevier]

Abstract: Glutathione (GSH) is present in all mammalian tissues and plays a crucial role in many cellular processes. The second and final step in the synthesis involves the formation of GSH from gamma-glutamylcysteine (γ-GC) and glycine and is catalyzed by glutathione synthetase (GS). GS deficiency is a rare autosomal recessive disorder, and is present in patients with a range of phenotypes, from mild hemolytic anemia and metabolic acidosis to severe neurologic disorders or even death in infancy. The substrate for GS, γ-GC, has been suggested as playing a protective role, by substituting for GSH as an antioxidant in GS deficient patients. To examine the role of GS and GSH metabolites in development, we generated mice deficient in GSH by targeted disruption of the GS gene (Gss). Homozygous mice died before embryonic day (E) 7.5, but heterozygous mice survived with no distinct phenotype. GS protein levels and enzyme activity, as well as GSH metabolites, were investigated in multiple tissues. Protein levels and enzyme activity of GS in heterozygous mice were diminished by 50%, while GSH levels remained intact. γ-GC could not be detected in any investigated tissue. These data demonstrate that GSH is essential for mammalian development, and GSH synthesis via GS is an indispensable pathway for survival. [Copyright &y& Elsevier]

Abstract: Pyruvate, a key intermediate in glucose metabolism, was explored as a potential treatment in models of experimental stroke and inflammation. Pyruvate was administered to rodents after the onset of middle cerebral artery occlusion (MCAO). Since the extent of inflammation is often proportional to the size of the infarct, we also studied a group of animals given lipopolysaccharide (LPS) to cause brain inflammation without cell death. Following MCAO, pyruvate did not affect physiological parameters but significantly reduced infarct volume, improved behavioral tests and reduced numbers of neutrophils, microglial and NFκB activation. Animals given LPS showed increased microglial and NFκB activation which was almost completely abolished by pyruvate. Lactate, a major metabolite of pyruvate, was increased after pyruvate administration. However, administration of lactate itself did not have any anti-inflammatory effects. Pyruvate protects against ischemia possibly by blocking inflammation, but lactate itself does not appear to explain pyruvate''s anti-inflammatory properties. [Copyright &y& Elsevier]