Target genes regulated by CLEC16A intronic region associated with common variable immunodeficiency.

BACKGROUND: CLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID). OBJECTIVES: This study sought to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID. METHODS: The investigators performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-sequencing to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using circular chromosome conformation capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-sequencing and reverse phase protein array. RESULTS: This study showed that the CLEC16A locus is an enhancer regulating expression of multiple target genes including a distant gene ATF7IP2 through chromatin interactions. Distinct transcription factor complexes mediate the chromatin interactions in an allele-specific manner. Disruption of the CLEC16A locus affects the AKT signaling pathway, as well as the molecular response of CD4+ T cells to immune stimulation. CONCLUSIONS: Through multiomics and targeted experimental approaches, this study elucidated the underlying target genes and signaling pathways involved in the genetic association of CLEC16A with CVID, and highlighted plausible molecular targets for developing novel therapeutics.

Fermentation-mediated variations in structure and biological activity of polysaccharides from Tetrastigma hemsleyanum Diels et Gilg.

Variations in the structure and activities of polysaccharides from Tetrastigma hemsleyanum Diels et Gilg fermented by Sanghuangporus sanghuang fungi were investigated. Compare with the unfermented polysaccharide (THDP2), the major monosaccharide composition and molecular weight of polysaccharide after fermentation (F-THDP2) altered dramatically, which caused galactose-induced conversion from glucose and one-third of molecular weight. F-THDP2 had a molecular weight of 1.23 × 104 Da. Moreover, the glycosidic linkage of F-THDP2 varied significantly, a 1, 2-linked α-d-Galp and 1, 2-linked α-d-Manp backbone was established in F-THDP2, which differed from that of 1, 4-linked α-d-Glcp and 1, 4-linked ß-d-Galp in THDP2. In addition, F-THDP2 showed a more flexible chain conformation than that of THDP2 in aqueous solution. Strikingly, F-THDP2 exhibited superior inhibitory effects on HeLa cells via Fas/FasL-mediated Caspase-3 signaling pathways than that of the original polysaccharide. These variations in both structure and biological activities indicated that fermentation-mediated modification by Sanghuangporus sanghuang might a promising novel method for the effective conversion of starch and other polysaccharides from Tetrastigma hemsleyanum Diels et Gilg into highly bioactive biomacromolecules, which could be developed as a potential technology for use in the food industry.

Molecular Characterization and Bioactivities of a Novel Polysaccharide from Phyllostachys pracecox Bamboo Shoot Residues.

Dietary carbohydrates are unexploited in the by-products of economically valuable Phyllostachys pracecox bamboo shoots. A residue-derived polysaccharide (PBSR1) was aqueously extracted from the processing waste of this bamboo shoot species. Its primary structure and advanced conformation were elucidated by a combined analysis of spectroscopy, chromatography, 2D nuclear magnetic resonance, laser light scattering and atomic microscopy. The results indicated PBSR1 was a triple-helix galactan consisting of →6)-ß-D-Galp and →3)-ß-D-Galp in linear with an 863 KD molecular weight (Mw). The relationship between the radius of gyration (Rg) and intrinsic viscosity ([η]) on Mw were established as Rg = 1.95 × 10-2Mw0.52±0.03 (nm) and [η] = 9.04 × 10-1Mw0.56±0.02 (mL/g) for PBSR1 in saline solution at 25 °C, which indicated it adopted a triple-helix chain shape with a height of 1.60 ± 0.12 nm supported by a red shift of λmax in Congo red analysis. The thermodynamic test (TG) displayed that it had excellent thermal stability for the food industry. Further, those unique structure features furnish PBSR1 on antioxidation with EC50 of 0.65 mg/mL on DPPH· and an ORAC value of 329.46 ± 12.1 µmol TE/g. It also possessed pronounced immunostimulation by up-regulating pro-inflammatory signals including NO, IL-6, TNF-α and IL-1ß in murine cells. Our studies provided substantial data for the high-valued application of residues and a better understanding of the structure-function relationship of polysaccharide.

Enhanced anaerobic hydrogen production from cotton straws assisted by copper molybdate.

Hydrogen production from dark fermentation has potential application due to its environmental friendliness, low production cost, and sustainability. However, there is still an obstacle to improving the efficiency of bioH2 production to meet the requirements in practical applications. In this research, copper molybdates are synthesized under different pH conditions as additives to study their different influence processes during anaerobic hydrogen production from cotton straws with the pure cultural system. A series of results indicate that CuMoO4 with appropriate experimental conditions has the highest H2 yield at 191.3 mL/g straws at 37 °C, which is 236% higher than the control group. It can be shown that O. ethanolica 8KG-4 has an obvious accompanying with high stability and low cytotoxicity for this clean energy production system as well as the improvement of metabolic pathway. These results extend new thinking of obtaining higher H2 yield as a biofuel in future production.

Ni(NH3)62+ more efficient than Ni(H2O)62+ and Ni(OH)2 for catalyzing water and phenol oxidation on illuminated Bi2MoO6 with visible light.

Nickel (hydr)oxide (NiOH) is known to be good co-catalyst for the photoelectrochemical oxidation of water, and for the photocatalytic oxidation of organics on different semiconductors. Herein we report a greatly improved activity of Bi2MoO6 (BMO) by nickel hexammine perchlorate (NiNH). Under visible light, phenol oxidation on BMO was slow. After NiNH, NiOH, and Ni2+ loading, a maximum rate of phenol oxidation increased by factors of approximately 16, 8.8, and 4.7, respectively. With a BMO electrode, all catalysts inhibited O2 reduction, enhanced water (photo-)oxidation, and facilitated the charge transfer at solid-liquid interface, respectively, the degree of which was always NiNH > NiOH > Ni2+. Solid emission spectra indicated that all catalysts improved the charge separation of BMO, the degree of which also varied as NiNH > NiOH > Ni2+. Furthermore, after a phenol-free aqueous suspension of NiNH/BMO was irradiated, there was a considerable Ni(III) species, but a negligible NH2 radical. Accordingly, a plausible mechanism is proposed, involving the hole oxidation of Ni(II) into Ni(IV), which is reactive to phenol oxidation, and hence promotes O2 reduction. Because NH3 is a stronger ligand than H2O, the Ni(II) oxidation is easier for Ni(NH3)6+ than for Ni(H2O)6+. This work shows a simple route how to improve BMO photocatalysis through a co-catalyst.

Conformation and anticancer activity of a novel mannogalactan from the fruiting bodies of Sanghuangporus sanghuang on HepG2 cells.

A novel water-soluble mannogalactan (SSPS1) with an average molecular weight of 2.04 × 104 Da was obtained from the fruiting bodies of the Sanghuangporus sanghuang. It revealed that SSPS1 was composed of d-galactose, d-mannose, l-fucose, 3-O-methylgalactose and d-glucose in a ratio of 6.2:3.9:3.1:2.1:1.0. The structural elucidation of SSPS1 consisted of 1, 6-linked α-D-Galp, 1, 6-linked α-D-Manp and 1, 6-linked 3-O-methyl-α-D-Galp backbone with branching at O-2 of 1, 6-α-D-mannosyl residues by α-L-Fucp and α-D-Glcp units. The conformational parameters suggested that a flexible chain conformation of SSPS1 in solution based on light scattering and atomic force microscopy imaging. Intriguingly, it presented potent anticancer activity on HepG2 cell with Rq and Ra values increased dramatically up to 73.93 nm and 53.92 nm compared with the control. The analysis of flow cytometry indicated SSPS1 could induce the apoptosis of HepG2 cells and arrest them via S phase. Western blot assay further uncovered that apoptosis process was triggered by SSPS1 via a mitochondria-mediated signaling pathway, which was evidenced by an increased ratio of Bax/Bcl-2, the release of cytochrome c and the strong activation of caspase-3 and 9. Taken together, these results suggested that SSPS1 might be applied in functional food as an anticancer agent.

Tumor Mutational Burden Associated With Response to Hyperthermic Intraperitoneal Chemotherapy.

Background: Gastric cancer (GC) is one of the most common cancer types, especially in Asian countries. Hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to improve the progression-free survival among gastric cancer patients with peritoneal metastases; however, not all patients demonstrate response to HIPEC. Methods: Biomarkers are needed to select patients for effective treatment of HIPEC. Here, we performed whole-exome sequencing on tumor samples from 18 gastric cancer patients who received HIPEC treatment and assessed the association between genomic mutation features and progression-free survival. Exome sequencing was further conducted on tumor samples from additional 15 gastric cancer patients as a replication study. Results: The tumor mutational burden (TMB) was significantly higher in the group of patients with a better response to HIPEC treatment than that of the others. Kaplan-Meier survival curve showed that patients with high TMB had a significantly longer survival time than that in patients with low TMB. This discovery was validated in the replication cohort. Genes bearing mutations recurrently and selectively in patients with better response to HIPEC were found in the two cohorts. Conclusion: We found that higher TMB is significantly associated with better response to HIPEC. Our results provide useful hints for prognostic stratification of HIPEC treatment.

Amorphous NiSn and FeOOH as bifunctional co-catalysts for oxygen reduction and phenol (water) oxidation over BiVO4 under visible light.

Monoclinic BiVO4 (BiV) has been widely used as a photoanode for water oxidation, but rarely as a photocatalyst for organic oxidation due to slow reaction of O2. In this work, BiV has been modified with poorly crystallized sFe and sNi, where sFe is FeOOH, and sNi is a mixture of Ni(OH)2 and polysulfide. Under light, sFe/BiV and sNi/BiV in aqueous solution were more active than BiV, respectively, not only for phenol oxidation but also for O2 reduction. Importantly, the rate of phenol oxidation obtained for sFe/sNi/BiV was larger than the sum of the rates measured for sFe/BiV and sNi/BiV, by a factor of approximately 1.5. Moreover, on a film electrode, O2 reduction had a current of sFe/sNi/BiV > sNi/BiV > sFe/BiV > BiV, while water (photo)oxidation had a current of sFe/sNi/BiV > sNi/BiV > sFe/BiV > BiV. A possible mechanism is proposed, involving formation of a reduced sulfur species for O2 reduction and an oxidized iron species for phenol oxidation. In sFe/sNi/BiV, there is a mutual promotion between the sNi-mediated electron transfer and the sFe-mediated hole transfer. This results in a further improved efficiency of charge separation for O2 reduction and phenol oxidation.

Characterization, immunostimulatory and antitumor activities of a ß-galactoglucofurannan from cultivated Sanghuangporus vaninii under forest.

A biomacromolecule, named as ß-galactoglucofurannan (SVPS2), was isolated from the cultivated parts of Sanghuangporus vaninii under the forest. Its primary and advanced structure was analyzed by a series of techniques including GC-MS, methylation, NMR, MALS as well as AFM. The results indicated that SVPS2 was a kind of 1, 5-linked ß-Glucofurannan consisting of ß-glucose, ß-galactose and α-fucose with 23.4 KDa. It exhibited a single-stranded chain with an average height of 0.72 nm in saline solution. The immunostimulation test indicated SVPS2 could facilitate the initiation of the immune reaction and promote the secretion of cytokines in vitro. Moreover, SVPS2 could mediate the apoptosis of HT-29 cells by blocking them in S phase. Western blot assay revealed an upregulation of Bax, Cytochrome c and cleaved caspase-3 by SVPS2, accompanied by a downregulation of Bcl-2. These results collectively demonstrate that antitumor mechanism of SVPS2 may be associated with enhancing immune response and inducing apoptosis of tumor cells in vitro. Therefore, SVPS2 might be utilized as a promising therapeutic agent against colon cancer and functional food with immunomodulatory activity.

Discovery of Novel Host Molecular Factors Underlying HBV/HCV Infection.

Hepatitis is an inflammatory condition of the liver, which is frequently caused by the infection of hepatitis B virus (HBV) or hepatitis C virus (HCV). Hepatitis can lead to the development of chronic complications including cancer, making it a major public health burden. Co-infection of HBV and HCV can result in faster disease progression. Therefore, it is important to identify shared genetic susceptibility loci for HBV and HCV infection to further understand the underlying mechanism. Through a meta-analysis based on genome-wide association summary statistics of HBV and HCV infection, we found one novel locus in the Asian population and two novel loci in the European population. By functional annotation based on multi-omics data, we identified the likely target genes at each novel locus, such as HMGB1 and ATF3, which play a critical role in autophagy and immune response to virus. By re-analyzing a microarray dataset from Hmgb1-/- mice and RNA-seq data from mouse liver tissue overexpressing ATF3, we found that differential expression of autophagy and immune and metabolic gene pathways underlie these conditions. Our study reveals novel common susceptibility loci to HBV and HCV infection, supporting their role in linking autophagy signaling and immune response.

CuCoOx/BiVO4 multifunctional catalyst for organics degradation, water oxidation, and O2 reduction under visible light.

Monoclinic BiVO4 (BiV) is an excellent photoanode for water oxidation, but it is a poor photocatalyst for organic oxidation due to slow O2 reduction. Herein we report a 94-fold increased photocatalytic activity of BiV through a surface deposited CuCoOx. The model reaction was phenol degradation in aqueous solution under visible light. CuCoOx, CuOx, and CoOx were prepared in butanol, separately, while CuCo2O4 was prepared in aqueous solution. Solid characterization showed that CuCo2O4 was Cu0.92Co2.08O4, but CuCoOx was a mixture of Cu0.92Co2.08O4, CuOx, and CoOx. Notably, the rate of phenol oxidation on CuCoOx/BiV was not only larger than those on Pt/BiV, CuCo2O4/BiV, CuOx/BiV, and CoOx/BiV, but also larger than the sum of the rates obtained for the latter three. Photoluminescence study revealed that all co-catalysts improved the efficiency of charge separation of BiV, with the trend similar to that for phenol photo-oxidation. Electrochemical study with a BiV film electrode showed that among four co-catalysts, CuOx was the most active for O2 reduction, CoOx for water oxidation, and CuCo2O4 for water photo-oxidation. According to the measured band edge potentials for semiconductors, a possible charge transfer from BiV to co-catalyst is proposed, including the electron transfer for CuOx/BiV, the hole transfer for CoOx/BiV and CuCo2O4/BiV, and the sequential electron transfer for CuCoOx/BiV.

Fast organic degradation on Ti- and Bi-based photocatalysts via co-deposited Pt and Ni3(PO4)2 nanoparticles.

Environmental remediation via semiconductor (SC) photocatalysis has attracted great attention over the past three decades. However, prospect for large scale application is still under debate, basically due to the bottleneck of fast charge recombination and/or slow surface reaction. Herein we report a universal solution of speeding up organic degradation simply via co-deposited Pt and nickel phosphate (NiP). Several representative SCs have been examined, including TiO2 (anatase, rutile, and brookite) under a 320 nm light, and Bi-based SC (BiVO4, Bi2WO6, and Bi2MoO6) under a 420 nm light. In all cases, the rates of phenol degradation in aqueous solution always varied not only in the order of NiP/Pt/SC > Pt/SC > NiP/SC > SC, but also NiP/Pt/SC > (Pt/SC + NiP/SC + SC). Meanwhile, hydroquinone and benzoquinone were produced as the main intermediates, but their concentration was much lower than that of phenol decreased, especially for NiP-containing sample. The solid was characterized with several techniques, including photoluminescence and (photo)electrochemical measurement. It is proposed that Pt and NiP act as co-catalysts for O2 reduction and phenol oxidation, respectively. Such electron and hole transfer promote each other, additionally improving the efficiency of charge separation, and further increasing the rates of surface reactions. This work highlights the necessity of a versatile co-catalyst in SC photocatalysis.

The Role of Autophagy in Skeletal Muscle Diseases.

Skeletal muscle is the most abundant type of tissue in human body, being involved in diverse activities and maintaining a finely tuned metabolic balance. Autophagy, characterized by the autophagosome-lysosome system with the involvement of evolutionarily conserved autophagy-related genes, is an important catabolic process and plays an essential role in energy generation and consumption, as well as substance turnover processes in skeletal muscles. Autophagy in skeletal muscles is finely tuned under the tight regulation of diverse signaling pathways, and the autophagy pathway has cross-talk with other pathways to form feedback loops under physiological conditions and metabolic stress. Altered autophagy activity characterized by either increased formation of autophagosomes or inhibition of lysosome-autophagosome fusion can lead to pathological cascades, and mutations in autophagy genes and deregulation of autophagy pathways have been identified as one of the major causes for a variety of skeleton muscle disorders. The advancement of multi-omics techniques enables further understanding of the molecular and biochemical mechanisms underlying the role of autophagy in skeletal muscle disorders, which may yield novel therapeutic targets for these disorders.

Inhibitory mechanism of two homoisoflavonoids from Ophiopogon japonicus on tyrosinase activity: insight from spectroscopic analysis and molecular docking.

The inhibition mechanism of two homoisoflavonoids from Ophiopogon japonicus including methylophiopogonanone A (MO-A) and methylophiopogonanone B (MO-B) on tyrosinase (Tyr) was studied by multiple spectroscopic techniques and molecular docking. The results showed that the two homoisoflavonoids both inhibited Tyr activity via a reversible mixed-inhibition, with a half inhibitory concentration (IC50) of (10.87 ± 0.25) × 10-5 and (18.76 ± 0.14) × 10-5 mol L-1, respectively. The fluorescence quenching and secondary structure change of Tyr caused by MO-A and B are mainly driven by hydrophobic interaction and hydrogen bonding. Molecular docking analysis indicated that phenylmalandioxin in MO-A and methoxy in MO-B could coordinate with a Cu ion in the active center of Tyr, and interacted with amino acid Glu322 to form hydrogen bonding, occupying the catalytic center to block the entry of the substrate and consequently inhibit Tyr activity. This study may provide new perspectives on the inhibition mechanism of MO-A and MO-B on Tyr and serve a scientific basis for screening effective Tyr inhibitors.

Structural characterization and hypoglycemic activity of an intracellular polysaccharide from Sanghuangporus sanghuang mycelia.

A neutral polysaccharide (SSIPS1) was isolated and purified from cultured mycelia of Sanghuangporus sanghuang by DEAE Sepharose Fast Flow and Sephacryl S-100 columns. Basic monosaccharide composition indicated that SSIPS1 was mainly composed of d-glucose. The results of methylation and 2D-NMR analysis suggested that the glycosidic linkages of SSIPS1 were elucidated to consisted of 1,4-linked α-d-glucopyranose (Glcp) residues with two branched points at O-6. The two branches were composed of 1,4-linked α-D-Glcp terminated with α-D-Glcp, 1,4-linked α-D-Glcp and 1,4-linked ß-Galp terminated by α-D-Glcp. Moreover, its chain conformation was revealed to present a flexible chain conformation in 0.1 NaNO3 with a hydrodynamic radius and radius of gyration of 3.26 and 6.45 nm by multi-angle laser light scattering, with a single chain of 0.559 nm observed by atomic force microscopy. Further, SSIPS1 exhibited a potential inhibitory activity against α-amylase and α-glucosidase, and it had hypoglycemic effects on in vitro insulin resistance of HepG2 cells as well.

Improved Performance of BiVO4 via Surface-Deposited Magnetic CuFe2O4 for Phenol Oxidation and O2 Reduction and Evolution under Visible Light.

Monoclinic BiVO4 (BiV) is a good photoanode for water oxidation but a poor photocatalyst for organic oxidation because of slow O2 reduction. In this work, a well-crystallized BiV microdecahedron (1-2 µm) has been deposited with a poorly crystallized cubic CuFe2O4 (CF) nanosphere (100 nm). For phenol oxidation and O2 reduction to H2O2 in aqueous suspension under visible light, 1 wt % CF/BiV was more active than BiV by approximately factors of 14 and 7, respectively, while CF was almost not active. A (photo)electrochemical measurement showed that CF/BiV was more active than BiV not only for phenol and water oxidation under visible light but also for O2 reduction and water oxidation in the dark. Moreover, as compared to BiV, CF/BiV was more efficient in the charge transfer to a solution species but less efficient either in the light-on electron generation or in the light-off electron disappearance. Based on the solid band edge potentials measured by ultraviolet photoelectron spectroscopy, a possible Z scheme mechanism is proposed involving charge recombination at the CF/BiV interfaces followed by the increased O2 reduction on CF and the increased phenol oxidation on BiV.