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TIGIT is an immune checkpoint receptor that is expressed on subsets of activated T cells and natural killer (NK) cells. Several ligands for TIGIT, including poliovirus receptor (PVR), are expressed on cancer cells and mediate inhibitory signaling to suppress antitumor activities of the immune cells. Many studies support that the TIGIT signaling is a potential target for cancer immunotherapy. We developed an IgG4-type monoclonal antibody against human TIGIT, designated as MG1131, using a phage display library of single-chain variable fragments (scFvs). MG1131 interacts with TIGIT much more tightly than PVR does. The crystal structure of a scFv version of MG1131 bound to TIGIT was determined, showing that MG1131 could block the PVR-TIGIT interaction and thus the immunosuppressive signaling of TIGIT. Consistently, MG1131 is bound to TIGIT-expressing cells and interferes with PVR binding to these cells. Moreover, MG1131 increased NK cell-mediated tumor killing activities, inhibited immunosuppressive activity of regulatory T (Treg) cells from healthy donors, and restored interferon-γ secretion from peripheral blood mononuclear cells derived from multiple myeloma patients. MG1131 also increased T cell infiltration to the tumor site and inhibited tumor growth in mice. Collectively, these data indicate that MG1131 modulates the effector functions of T cells and NK cells positively and Treg cells negatively.

Abstract Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders that are highly heterogeneous in clinical symptoms as well as etiologies. Mutations in SHANK2 are associated with ASD and accordingly, Shank2 knockout mouse shows ASD-like behavioral phenotypes, including social deficits. Intriguingly, two lines of Shank2 knockout (KO) mouse generated by deleting different exons (exon 6–7 or exon 7) showed distinct cellular phenotypes. Previously, we compared gene expressions between Shank2 KOs lacking exon 6–7 (e6–7 KO) and KOs lacking exon 7 (e7 KO) by performing RNA-seq. In this study, we expanded transcriptomic analyses to identify novel transcriptional variants in the KO mice. We found prominent expression of a novel exon (exon 4′ or e4’) between the existing exons 4 and 5 in the Shank2 e6–7 KO model. Expression of the transcriptional variant harboring this novel exon was confirmed by RT-PCR and western blotting. These findings suggest that the novel variant may function as a modifier gene, which contributes to the differences between the two Shank2 mutant lines. Furthermore, our result further represents an example of genetic compensation that may lead to phenotypic heterogeneity among ASD patients with mutations in the same gene.

Abstract Background Effective control of shot-hole disease in flowering cherries is challenging because of multiple causative pathogens (bacteria and fungi). Bacillus species are well-known for their ability to control plant pathogens; therefore, biological control potential of a Bacillus isolate, B. velezensis 8–2, against SH disease on flowering cherry trees was investigated. Results This study revealed strong antimicrobial activity of Bacillus velezensis 8–2 against various plant pathogenic bacteria and fungi, particularly focusing on Xanthomonas arboricola pv. pruni (Xap) and Mycosphaerella cerasella (Mc), which cause shot-hole (SH) disease in flowering cherry trees. In vitro assays showed that the fermentation filtrate of B. velezensis 8–2 inhibited bacterial and fungal growth with minimum inhibitory concentrations of 1.25–10% and 2.5–10%, respectively. UPLC-Q–Orbitrap–MS analysis revealed that B. velezensis 8–2 produced antagonistic compounds, including polyketides (difficidin and oxydifficidin) and cyclic lipopeptides (iturin A, fengycin, and surfatin). To enhance antimicrobial activity, fermentation parameters for optimal production of two antibacterial and three antifungal compounds were investigated in a 5 L jar fermenter. By regulating the agitation speed to sustain the state of vegetative cells, the production period was extended by 20 h at 400 rpm, resulting in maximum yields of 86.6 μg/mL for difficidin and 150.0 μg/mL for oxydifficidin within a 72 h fermentation period. In a field trial, a 500-fold diluted 10% suspension concentrate formulation of B. velezensis 8–2 effectively inhibited the development of SH disease, demonstrating 66.6% disease control and a 90.2% disease symptoms reduction. Conclusions This is the first report to assess the disease control efficacy of B. velezensis for the biocontrol of SH disease in the field. These results suggest that the application of B. velezensis 8–2 could serve as a practical alternative for managing various bacterial and fungal diseases, including the management of SH disease in flowering cherry trees. Graphical Abstract

Cohen syndrome (CS), a rare autosomal recessive disorder, has been associated with genetic mutations in the VPS13B gene, which regulates vesicle-mediated protein sorting and transport. However, the cellular mechanism underlying CS pathogenesis in patient-derived human neurons remains unknown. We identified a novel compound heterozygous mutation, due to homozygous variation of biparental origin and heterozygous variation inherited from the father, in the VPS13B gene in a 20-month-old female patient. To understand the cellular pathogenic mechanisms, we generated induced pluripotent stem cells (iPSCs) from the fibroblasts of the CS patient. The iPSCs were differentiated into forebrain-like functional glutamatergic neurons or neurospheres. Functional annotation from transcriptomic analysis using CS iPSC-derived neurons revealed that synapse-related functions were enriched among the upregulated and downregulated genes in the CS neurons, whereas processes associated with neurodevelopment were enriched in the downregulated genes. The developing CS neurospheres were small in size compared to control neurospheres, likely due to the reduced proliferation of SOX2-positive neural stem cells. Moreover, the number of SV2B-positive puncta and spine-like structures was significantly reduced in the CS neurons, suggesting synaptic dysfunction. Taking these findings together, for the first time, we report a potential cellular pathogenic mechanism which reveals the alteration of neurodevelopment-related genes and the dysregulation of synaptic function in the human induced neurons differentiated from iPSCs and neurospheres of a CS patient.

Lactic acid bacteria (LAB) are being used for probiotic and starter cultures to prevent global damage to microbial cells. To retain the benefits of LAB in the commercially used powdered form, highly efficient cryoprotective agents are required during the manufacturing process. This study suggests a novel cryoprotective agent derived from Jerusalem artichoke (JA; Helianthus tuberous L.) and describes the mechanism of cryoprotective effect improvement by sonication treatment. The cryoprotective effect of JA extract was verified by examining the viability of Leuconostoc mesenteroides WiKim33 after freeze-drying (FD). Sonication of JA extract improved the cryoprotective effect. Sonication reduced fructose and glucose contents, which increased the induction of critical damage during FD by 15.84% and 46.81%, respectively. The cryoprotective effects of JA and sonication-treated JA extracts were determined using the viable cell count of Leu. mesenteroides WiKim33. Immediately after FD and storage for 24 weeks, the viability of Leu. mesenteroides WiKim33 with JA extract was 82.8% and 76.3%, respectively, while that of the sonication-treated JA extract was 95.2% and 88.8%, respectively. Our results show that reduction in specific monosaccharides was correlated with improved cryoprotective effect. This study adopted sonication as a novel treatment for improving the cryoprotective effect and verified its efficiency.

Increasing concerns regarding the adverse effects of radioactive iodine waste have inspired the development of a highly efficient and sustainable desalination process for the treatment of radioactive iodine-contaminated water. Because of the high affinity of silver towards iodine species, silver nanoparticles immobilized on a cellulose acetate membrane (Ag-CAM) and biogenic silver nanoparticles containing the radiation-resistant bacterium Deinococcus radiodurans (Ag-DR) were developed and investigated for desalination performance in removing radioactive iodines from water. A simple filtration of radioactive iodine using Ag-CAM under continuous in-flow conditions (approximately 1.5 mL/s) provided an excellent removal efficiency (>99%) as well as iodide anion-selectivity. In the bioremediation study, the radioactive iodine was rapidly captured by Ag-DR in the presence of high concentration of competing anions in a short time. The results from both procedures can be visualized by using single-photon emission computed tomography (SPECT) scanning. This work presents a promising desalination method for the removal of radioactive iodine and a practical application model for remediating radioelement-contaminated waters. [ABSTRACT FROM AUTHOR]

Aromatic polyesters are widely used plastics currently produced from petroleum. Here we engineer Escherichia coli strains for the production of aromatic polyesters from glucose by one-step fermentation. When the Clostridium difficile isocaprenoyl-CoA:2-hydroxyisocaproate CoA-transferase (HadA) and evolved polyhydroxyalkanoate (PHA) synthase genes are overexpressed in a D-phenyllactate-producing strain, poly(52.3 mol% 3-hydroxybutyrate (3HB)-co-47.7 mol% D-phenyllactate) can be produced from glucose and sodium 3HB. Also, various poly(3HB-co-D-phenyllactate) polymers having 11.0, 15.8, 20.0, 70.8, and 84.5 mol% of D-phenyllactate are produced from glucose as a sole carbon source by additional expression of Ralstonia eutropha β-ketothiolase (phaA) and reductase (phaB) genes. Fed-batch culture of this engineered strain produces 13.9 g l-1 of poly(61.9 mol% 3HB-co-38.1 mol% Dphenyllactate). Furthermore, different aromatic polyesters containing D-mandelate and D-3- hydroxy-3-phenylpropionate are produced from glucose when feeding the corresponding monomers. The engineered bacterial system will be useful for one-step fermentative production of aromatic polyesters from renewable resources. [ABSTRACT FROM AUTHOR]

Myrcene is an aromatic volatile compound that is commercially well-known as a flavor ingredient in the food industry and a fragrance in the soap and detergent industry. Given the worldwide interest in natural antiphotoaging products, we investigated the protective effects of myrcene in UVB-irradiated human dermal fibroblasts (NHDFs). NHDFs were subjected to 144 mJ/cm²of UVB irradiation. The expression of intracellular reactive oxygen species (ROS), matrix metalloproteinase-1 (MMP-1), MMP-3, interleukin-6 (IL-6), transforming growth factor (TGF-ß1) and type I procollagen were examined. We showed that myrcene decreased the production of ROS, MMP-1, MMP-3, and IL-6, and increased TGF-ß1 and type I procollagen secretions. Furthermore, myrcene treatment (0.1-10 µM) dramatically reduced the activation of MAPK-related signaling molecules such as p-ERK, p-p38, and p-JNK and AP-1 including p-c-Jun and p-c-Fos. Our data indicate that myrcene has a potential protective effect on UVB-induced human skin photoaging. Therefore, myrcene might have applications in the skincare industry. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex (TSC) is a neurocutaneous disorder characterized by multiple symptoms including neuropsychological deficits such as seizures, intellectual disability, and autism. TSC is inherited in an autosomal dominant pattern and is caused by mutations in either the TSC1 or TSC2 genes, which enhance activation of the mammalian target of rapamycin (mTOR) signaling pathway. Recent studies have suggested that mTOR inhibitors such as rapamycin can reverse TSC-associated deficits in rodent models of TSC. In addition, clinical trials are ongoing to test the efficacy of mTOR inhibitors toward the psychiatric symptoms associated with TSC. Here, we report a case study of a Korean patient with TSC, who exhibited multiple symptoms including frequent seizures, intellectual disability, language delays, and social problems. We performed whole exome sequencing and identified a novel small deletion mutation in TSC2. Expressing the novel deletion mutant in HEK293T cells significantly increased mTOR pathway activation. Furthermore, everolimus treatment showed not only reduction in SEGA size, but dramatically improved behavioral deficits including autism related behaviors in the patient. In summary, we identified a novel small deletion mutation in TSC2 associated with severe TSC in a Korean family that enhances the activation of mTOR signaling in vitro. Everolimus treatment improved behavioral deficits in the patient. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social cognition, language development, and repetitive/restricted behaviors. Due to the complexity and heterogeneity of ASD and lack of a proper human cellular model system, the pathophysiological mechanism of ASD during the developmental process is largely unknown. However, recent progress in induced pluripotent stem cell (iPSC) technology as well as in vitro neural differentiation techniques have allowed us to functionally characterize neurons and analyze cortical development during neural differentiation. These technical advances will increase our understanding of the pathogenic mechanisms of heterogeneous ASD and help identify molecular biomarkers for patient stratification as well as personalized medicine. In this review, we summarize our current knowledge of iPSC generation, differentiation of specific neuronal subtypes from iPSCs, and phenotypic characterizations of human ASD patient-derived iPSC models. Finally, we discuss the current limitations of iPSC technology and future directions of ASD pathophysiology studies using iPSCs. [ABSTRACT FROM AUTHOR]

The article presents a study on the effects on human hair dermal papilla cells (HHDPCs) and on the stimulation of air growth in a cyclophosphamide (CYP)-induced alopecia model C57BL/6 mouse of Cuscuta japonica BuOH fraction (CJBF). An increase in the number of hair follicles and the thickness of the epidermis were observed in the groups treated in CJBF. It was found that in HHDPCs and C57BL/6, CJBF promotes hair growth and retards the catagen phase.

Purpose: To investigate the protective effect of Gastrodia elata Blume (G. elata, GE) and cyclodextrin glucanotransferase (CGTase) enzyme-treated G. elata extract (EGE) against premature skin aging using ultraviolet B (UVB)-exposed normal human dermal fibroblasts (NHDFs). Methods: The extract was characterized by liquid chromatography with tandem mass spectrometry (LC-MS/MS), ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QToF-MS) and nuclear magnetic resonance spectroscopy (NMR). The expression of matrix metalloproteinases (MMP-1,3), interleukin-6 (IL-6), transforming growth factor (TGF-β1) and procollagen type I was assayed using ELISA kits. Safety evaluation of EGE's dietary administration and topical application was performed by in vivo acute oral toxicity and local lymph node tests. Results: Lower MMP-1 and IL-6 and higher procollagen type I and TGF-β1 levels were observed after treatment with EGE than with GE, indicating that EGE was more effective than GE in treating UVBinduced photoaging. With respect to phenolic composition, EGE had lower 4-hydroxybenzaldehyde (4- HBA) level and higher a-gastrodin level than GE. In UVB-irradiated NHDFs, a-gastrodin exhibited higher anti-aging activity than 4-HBA and β-gastrodin based on the expression of MMP-1, MMP-3, and procollagen type I. The in vivo data indicate that EGE was safe at concentrations of up to 2000 mg/kg for dietary administration and 0.1% for topical application. Conclusion: EGE protects UVB-induced photoaged human skin better than GE owing to its higher α- gastrodin content. Thus, EGE may be potentially useful agent in anti-aging cosmetic products. [ABSTRACT FROM AUTHOR]

Xanthophylls, a yellow pigment belonging to the carotenoid family, have attracted much attention for industrial applications due to their versatile nature. We report the isolation of a homo xanthophyll pigment-producing marine bacterium, identified as the Erythrobacter sp. SDW2 strain, from coastal seawater. The isolated Erythrobacter sp. SDW2 strain can produce 263 ± 12.9 mg/L (89.7 ± 5.4 mg/g dry cell weight) of yellow xanthophyll pigment from 5 g/L of glucose. Moreover, the xanthophyll pigment produced by the SDW2 strain exhibits remarkable antioxidative activities, confirmed by the DPPH (73.4 ± 1.4%) and ABTS (84.9 ± 0.7%) assays. These results suggest that the yellow xanthophyll pigment-producing Erythrobacter sp. SDW2 strain could be a promising industrial microorganism for producing marine-derived bioactive compounds with potential for foods, cosmetics, and pharmaceuticals.

As concerns are increasing about drinking water contamination with heavy metals, we investigated the possible use of a pellicle (floating biofilm)-like biofilm-producing microorganism as a biosorbent for the treatment of Pb(II) in aqueous solutions. The bacterial pellicle-producing Methylobacterium hispanicum EM2 strain (EM2) was newly isolated from mine tailing soil, and we investigated its use as a biosorbent for treating a Pb(II)-contaminated aqueous solution. The EM2 strain was strongly resistant to Pb(II) up to a concentration of 800 mg/L, and achieved remarkable adsorption performance (adsorption rate and maximum adsorption capacity of 96% ± 3.2% and 79.84 mg/g, respectively) under optimal conditions (pH, biomass content, contact time, and initial Pb(II) concentration of 7.1 g/L, 60 min, and 10 mg/L, respectively). The adsorption of Pb(II) was characterized by scanning electron microscopy-energy dispersive x-ray spectroscopy and Fourier-transform infrared analysis. The equilibrium data matched the Freundlich isotherm model well, indicating the occurrence of multilayer adsorption of Pb(II) onto the heterogeneous surface of the EM2 strain, which was also consistent with the pseudo-second-order kinetic model (R2 = 0.98). The high Pb(II) removal efficiency was also confirmed by conducting an adsorption experiment using Pb(II)-contaminated industrial wastewater.

This paper describes a novel chromatographic method for efficient removal of anionic dyes from aqueous solutions. Chitosan-coated Fe3O4 nanoparticles can easily be immobilized on a dextran gel column. Single elution of Evans Blue (EB) solution to the nanoadsorbent-incorporated columns provides high removal efficiency with a maximum adsorption capacity of 243.9 mg/g. We also investigated the influence of initial concentration and solution pH on the removal efficiency of EB. The electrostatic interaction between the adsorbent surface and negatively charged sulfate groups on EB molecules promotes the efficient adsorption of dyes. The equilibrium data matched well with the Langmuir isotherm model, which indicated monolayer dye adsorption onto the adsorbent surface. To extend the application of the current method, we performed further adsorption experiments using other anionic dyes of different colors (Cy5.5, Acid Yellow 25, Acid Green 25, and Acid Red 1). All of these molecules can efficiently be captured under continuous flow conditions, with higher removal efficiency obtained with more negatively charged dyes. These findings clearly demonstrate that the present approach is a useful method for the removal of anionic dye contaminants in aqueous media by adsorption.

As concerns about public health and environmental problems regarding contamination by toxic substances increase worldwide, the development of a highly effective and specific treatment method is imperative. Although physicochemical arsenic treatment methods have been developed, microbial in vivo remediation processes using live cell fabricated nanoparticles have not yet been reported. Herein, we report the development of magnetic iron nanoparticles immobilized an extremophilic microorganism, Deinococcus radiodurans R1, capable of removing toxic arsenic species. First, in vivo synthesis of magnetic iron nanoparticles was successfully achieved with the D. radiodurans R1 strain and characterized by scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX), dynamic light scattering (DLS), zeta-potential, Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) analysis. Second, the maximum removal capacity of the magnetic iron nanoparticle-immobilized D. radiodurans R1 strain (DR-FeNPs) for arsenic [As(V)] was evaluated under the optimized conditions. Finally, the removal capacity of DR-FeNPs in the presence of various competitive anions was also investigated to simulate the practical application. More than 98% of As(V) was efficiently removed by DR-FeNPs within 1 h, and the removal efficiency was stably maintained for up to 32 h (98.97%). Furthermore, the possibility of recovery of DR-FeNPs after use was also suggested using magnets as a proof-of-concept.