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The expression of voltage-gated potassium Kv1.3 channels is increased in activated microglia, with non-selective blockade reported to attenuate microglial-mediated neuroinflammation. In this study, we evaluated the impact of a potent and selective peptidic blocker of Kv1.3 channels, HsTX1[R14A], on microglial-mediated neuroinflammation in vitro and in vivo. Treatment with both 0.1 and 1 µg/mL lipopolysaccharide (LPS) significantly (p

The natural concentration of bovine lactoferrin C-lobe is low and its separation by proteolytic enzyme digestion is difficult. Here, we expressed the codon-optimized fragment of C-lobe on plasmid pMA0911 with the Pveg promoter in Bacillus subtilis 168 at 20 °C. The yield was 7.5 mg/L, and 90.6% purity was achieved using ammonium sulfate precipitation, Ni–NTA and molecular exclusion. The C-lobe at 10 mg/mL completely inhibited cell growth of Escherichia coli JM109 (DE3) and Pseudomonas aeruginosa CGMCC 1.6740, and 48.4% of growth of Staphylococcus aureus CGMCC 1.282, the result is similar to that of 200 ng/mL N-lobe. The minimum inhibitory concentrations of C-lobe were 4, 8 and 16 mg/mL, while those of N-lobe were 128, 256 and 512 μg/mL for E. coli, P. aeruginosa and S. aureus, respectively. This is the first report on bovine lactoferrin C-lobe expression and the comparative resistance of the recombinant N- and C-lobes in a food-safe strain of B. subtilis. Our findings offer the potential to study the structure–function relationship of the N- and C-lobes recombinantly produced in the same host.

Side-chain giant molecules, constructed from giant monomers by precision synthesis, are viewed as a size-amplified analogue of conventional linear polymers. The molecular accuracy in terms of compo...

Protein citrullination (deimination of arginine residue) is a well-known biomarker of inflammation. Elevated protein citrullination has been shown to colocalize with extracellular amyloid plaques in postmortem AD patient brains. Amyloid-β (Aβ) peptides which aggregate and accumulate in the plaques of Alzheimer's disease (AD) have sequential N-terminal truncations and multiple post-translational modifications (PTM) such as isomerization, pyroglutamate formation, phosphorylation, nitration, and dityrosine cross-linking. However, no conclusive biochemical evidence exists whether citrullinated Aβ is present in AD brains. In this study, using high-resolution mass spectrometry, we have identified citrullination of Aβ in sporadic and familial AD brains by characterizing the tandem mass spectra of endogenous N-truncated citrullinated Aβ peptides. Our quantitative estimations demonstrate that ∼ 35% of pyroglutamate3-Aβ pool was citrullinated in plaques in the sporadic AD temporal cortex and ∼ 22% in the detergent-insoluble frontal cortex fractions. Similarly, hypercitrullinated pyroglutamate3-Aβ (∼ 30%) was observed in both the detergent-soluble as well as insoluble Aβ pool in familial AD cases. Our results indicate that a common mechanism for citrullination of Aβ exists in both the sporadic and familial AD. We establish that citrullination of Aβ is a remarkably common PTM, closely associated with pyroglutamate3-Aβ formation and its accumulation in AD. This may have implications for Aβ toxicity, autoantigenicity of Aβ, and may be relevant for the design of diagnostic assays and therapeutic targeting.

The efficient stereoselective synthesis of conjugated dienes, especially those with axial chirality, remains a great challenge. Herein, we report the highly atroposelective synthesis of axially chiral styrenes with a conjugated 1,3-diene scaffold via a Pd(II)-catalyzed thioether-directed alkenyl C-H olefination strategy. This strategy features easy operation, mild reaction conditions, high functional group tolerance (69 examples), complete Z-selectivity, and excellent enantioselectivities (up to 99% ee). Notably, the highly enantioselective synthesis of atropisomers with two stereogenic axes were also achieved using this strategy (up to 99% ee and 97:3 dr). Moreover, the reaction could be scaled up, and the resulting axially chiral styrenes could be easily oxidized into chiral sulfoxide derivatives with high diastereoselectivities, which showed great promise as a new type of sulfur-olefin ligand.

KV1.3 is a voltage-gated potassium channel that is upregulated in neuroinflammatory conditions, such as Alzheimer's disease and Parkinson's disease. HsTX1[R14A] is a potent and selective peptide blocker of KV1.3 with the potential to block microglial KV1.3, but its brain uptake is expected to be limited owing to the restrictive nature of the blood-brain barrier. To assess its peripheral and brain exposure, a LC-MS/MS assay was developed to quantify HsTX1[R14A] concentrations in mouse plasma and brain homogenate that was reliable and reproducible in the range of 6.7–66.7 nM (r2 = 0.9765) and 15–150 pmol/g (r2 = 0.9984), respectively. To assess if neuroinflammation affected HsTX1[R14A] disposition, C57BL/6 mice were administered HsTX1[R14A] subcutaneously (2 mg/kg) 24 h after an intraperitoneal dose of Escherichia coli lipopolysaccharide (LPS), which is commonly used to induce neuroinflammation; brain and plasma concentrations of HsTX1[R14A] were then quantified over 120 min. LPS treatment significantly retarded the decline in HsTX1[R14A] plasma concentrations, presumably as a result of reducing renal clearance, and led to substantial brain uptake of HsTX1[R14A], presumably through disruption of brain inter-endothelial tight junctions. This study suggests that HsTX1[R14A] may reach microglia in sufficient concentrations to block KV1.3 in neuroinflammatory conditions, and therefore has the potential to reduce neurodegenerative diseases.

sA new sanggenon-type flavanone, nigragenon F (1), together with 11 known compounds, trans-resveratrol (2), (E)-4-isopentenyl-3,5,2′,4′-tetrahydroxystilbene (3), notabilisin E (4), notabilisin A (5), morusin (6), petalopurpurenol (7), 8-geranyl-5,7-dihydroxycoumarin (8), 2,4-dihydroxybenzaldehyde (9), 4-ethoxy-2,6-dihydroxybenzoic acid (10), 3-hydroxy-4-methoxybenzaldehyde (11), and 4-hydroxybenzaldehyde (12), were isolated from the stems of Morus nigra. Compound 10 was a new natural product, compounds 3, 4, 7, and 8 were reported from the Morus genus for the first time. All of the isolated compounds were evaluated for their α-glucosidase inhibition activity. Among them, six compounds showed obvious inhibitory effects against α-glucosidase with IC50 values ranging from 1.24 to 19.00 µmol/L.

This study evaluated the impact of poly(lactic-co-glycolic acid) (PLGA) microsphere formulations on in vitro release and in vivo plasma exposure of HsTX1[R14A], a potent inhibitor of the voltage-gated potassium channel Kv1.3, with potential to treat autoimmune conditions. Microspheres containing HsTX1[R14A] were prepared using different PLGA materials, including Resomer® RG502H, RG503H and PURASORB® PDLG 5004 (Purac). After assessing encapsulation efficiency and in vitro release, plasma concentrations of HsTX1[R14A] were quantified by LCMS/MS following subcutaneous administration of HsTX1[R14A]-loaded RG503H microspheres (15 mg/kg) or HsTX1[R14A] solution (4 mg/kg) to Sprague-Dawley rats. Microspheres prepared with Purac exhibited the greatest encapsulation efficiency (45.5 ± 2.4% (mean ± SD)) and RG502H the lowest (22.0 ± 6.4%). Release of HsTX1[R14A] was fastest in vitro for RG502H microspheres (maximum release at 31 days) and slowest for Purac (82 days). With a relatively rapid burst release of 20.0 ± 0.4% and a controlled release profile of up to 41 days, HsTX1[R14A]-loaded RG503H microspheres were selected for subcutaneous administration, resulting in detectable plasma concentrations for 11 days relative to 8 h following subcutaneous administration of HsTX1[R14A] solution. Therefore, subcutaneous administration of RG503H PLGA microspheres is a promising approach to be exploited for delivery of this immune modulator.

The performance of 2D nanomaterials hinges on both the chemical compositions and the morphological structures across different length scales. Among all the three dimensions, thickness is the only one that falls into the nanometer scale and, to some extent, determines the intrinsic properties of 2D nanomaterials. In this study, we report the preparation and precise thickness control of 2D nanosheets assembled from a library of monodispersed amphiphilic giant molecules composed of functional polyhedral oligomeric silsesquioxanes (POSSs) as the side groups. Solution self-assembly of such giant molecules resulted in 2D nanosheets with similar structural configurations, where a bilayer of hydrophobic isobutyl POSS (BPOSS) is sandwiched by two monolayers of hydrophilic POSS bearing carboxylic acid groups (APOSS). The thickness of the obtained nanosheets could be tuned through adjusting the chemical compositions of the pendant POSS cages. Intriguingly, we found that the thickness of the 2D nanosheets was not necessarily proportional to the contour length of the giant molecule nor the total number of POSS cages tethered to the main chain. Indeed, the number ratio of BPOSS to APOSS, rather than the exact number, played a deterministic role in the thickness control. To explain the unusual thickness dependence, we built up a structure model with an in-plane orientation of the giant molecules in the nanosheets, from which a formula was further deduced to semi-quantitatively describe the inverse relationship between the overall thickness and the number ratio of BPOSS to APOSS., Thickness of self-assembled 2D nanosheets is not necessarily proportional to the contour length (or molecular weight) of the building blocks.

By changing the transition metals (TMs) and polyanions, six polyoxometalate (POM)-based complexes 1–6 were synthesized by the hydrothermal method, namely [CdII(L1)2(HPMo12O40)]·2H2O (1), {MII2(H2O)4(L1)2[H2(β-Mo8O26)]}n·xH2O (n = 1, x = 1, M = Co (2), Cu (3), Fe (4); n = 0.5, x = 0, M = Ni (5), Zn (6)). The organic component 3,5-bis-(2,5-dihydro-imidazole-1-yl)benzoic acid (L1) is a tripodal ligand containing two imidazole and one carboxylic acid group. The N donors in the imidazole groups and the O donors in the carboxylic acid group of L1 can coordinate with different transition metal atoms to construct POM-based complexes. In complex 1, the Keggin anions are linked by [Cd(L1)2]2+ subunits to construct a chain. Complexes 2–6 are isostructural with [β-Mo8O26]4− anions linked by double metal–organic chains to build a 2D layer. The electrochemical behaviour and photocatalytic properties of these complexes were studied. These complexes can be used as amperometric sensors for the amperometric detection of Cr(VI), Fe(III) and H2O2. Moreover, these complexes can be used for fluorescence selective sensing of Cr3+.

High color purity with narrow-band emission is a key factor for full-color displays. However, phosphorescent metal complexes typically exhibit broad emission with a full width at half maxima (FWHM) in the range of 80–100 nm. Here, we demonstrate a facile approach to achieve narrow-band emission by introducing electron-deficient moieties with electron-transport character into PtAg2 heteronuclear complexes. The as-synthesized PtAg2 complex 3 with dibenzo[b,d]thiophene 5,5-dioxide-3-acetylide shows extremely narrow emission with an FWHM of 25 nm in CH2Cl2 solution. The narrow-band emission is further verified by another two PtAg2 complexes containing electron-transport units such as oxadiazole (complex 4) and triphenyl-triazine (complex 5), in which the FWHM values are 26 nm for 4 and 28 nm for 5 in CH2Cl2 solution. TD-DFT studies suggest that the involvement of intra-ligand transition within an electron-deficient acetylide ligand is likely responsible for the narrow-band emission. Solution-processed OLEDs based on complex 4 exhibit excellent device performance with an FWHM of 37 nm in the electroluminescent spectrum and the highest current efficiency (CE) of 69.5 cd A−1, power efficiency (PE) of 50.5 lm W−1 and external quantum efficiency (EQE) of 18.2%. The narrow-band electroluminescence is also attained in complexes 3 and 5 with the FWHM values of 31 and 40 nm, respectively, which represent the narrowest electroluminescence for multinuclear metal complexes. This strategy of introducing electron-transport moieties not only improves the device performance but also narrows the emission width and thus enhances the color purity.

Five polyoxometalate-based compounds were synthesized under hydrothermal conditions, namely [Cu3(OH)4(Ptla)2(H4TeMo6O24)]·3H2O (1), [Cu2(talm)2(H6TeMo6O24)]·6H2O (2), {Cu2(OH)(Ptep)2[H(β-Mo8O26)]}·2H2O (3), [Cu(bimeb)(H2O)2][(β-Mo8O26)0.5] (4), and [Cu5(OH)2(Ptpi)2(H2O)6][H4(TeMo6O24)2] (5) (Ptla = 2-(3-pyridin-4-yl-[1,2,4]triazol-4-yl)-ethylamine, talm = Tris(2-aminoethyl)amine, Ptep = 1-[2-(3-pyridin-4-yl-[1,2,4]triazol-4-yl)-ethyl]-piperazine, bimeb = 3,5-bis(imidazol-1-yl)methylbenzene, Ptpi = 1-[2-(3-pyridin-4-yl-[1,2,4]triazol-4-yl)-propyl]-imidazol). Compounds 1, 2 and 5 are all based on Anderson anions. In compound 1, the trinuclear Cu clusters link anions to form a 2D layer. Adjacent layers are further connected by Ptla ligands to construct a 3D framework. Compound 2 exhibits a 2D grid layer with [TeMo6O24]6− anions linked by [Cu(talm)]2+ subunits. Both triazol and pyridine groups of Ptpi coordinate with Cu atoms, inducing the 3D framework of 5. Compounds 3 and 4 are based on β-Mo8 anions. In compound 3, the Ptep ligands are linked by Cu atoms to build a cycle-connecting-cycle chain and the β-Mo8 anions are discrete. In compound 4, the Cu atoms connect infinite [Cu(bimeb)]nn+ chains to form a 3D structure. These five compounds can be used as amperometric detectors to detect NO2− and H2O2, especially 3 and 4 which can detect the cation Cr(VI). Additionally, the title compounds possess excellent photocatalytic activity, which can not only photocatalytically degrade organic dyes, but also can photocatalytically reduce Cr(VI) especially compounds 3 and 4.

Under hydrothermal conditions, a {PMo6O24N4}-based compound functionalized by 1,3-bis(1,3,4-triazole-1-methyl) benzene (btmbz) has been synthesized, namely {[Cd3(H2O)8]·[H4PMo6O24(btmbz)]2}·H2O (1). The Mo–N bonds assist the construction of the {PMo6O24N4} subunit. The photocatalytic and fluorescence sensing properties were studied.

Development of stretchable wearable devices requires essential materials with high level of mechanical and electrical properties as well as scalability. Recently, silicone rubber-based elastic polymers with incorporated conductive fillers (metal particles, carbon nanomaterials, etc.) have been shown to the most promising materials for enabling both high electrical performance and stretchability, but the technology to make materials in scalable fabrication is still lacking. Here, we propose a facile method for fabricating a wearable device by directly coating essential electrical material on fabrics. The optimized material is implemented by the noncovalent association of multiwalled carbon nanotube (MWCNT), carbon black (CB), and silicon rubber (SR). The e-textile sensor has the highest gauge factor (GF) up to 34.38 when subjected to 40% strain for 5,000 cycles, without any degradation. In particular, the fabric sensor is fully operational even after being immersed in water for 10 days or stirred at room temperature for 8 hours. Our study provides a general platform for incorporating other stretchable elastic materials, enabling the future development of the smart clothing manufacturing.

Background and aims Endoplasmic reticulum (ER) stress is an adaptive response to excessive ER demand and contributes to the development of numerous diseases, including nonalcoholic fatty liver disease (NAFLD), which is hallmarked by the accumulation of lipid within hepatocytes. However, the underlying mechanisms remain elusive. MicroRNAs (miRNAs) play an indispensable role in various stress responses, but their implications in ER stress have not yet been systemically investigated. In this study, we identify a negative feedback loop consisting of hepatic ER stress and miR-26a in NAFLD pathogenesis. Approach and results Combining miRNA dot blot array and quantitative PCR, we find that miR-26a is specifically induced by ER stress in liver cells. This induction of miR-26a is critical for cells to cope with ER stress. In human hepatoma cells and murine primary hepatocytes, overexpression of miR-26a markedly alleviates chemical-induced ER stress, as well as palmitate-triggered ER stress and lipid accumulation. Conversely, deficiency of miR-26a exhibits opposite effects. Mechanistically, miR-26a directly targets the eukaryotic initiation factor 2α, a core ER stress effector controlling cellular translation. Intriguingly, miR-26a is reduced in the livers of patients with NAFLD. Hepatocyte-specific restoration of miR-26a in mice significantly mitigates high-fat diet-induced ER stress and hepatic steatosis. In contrast, deficiency of miR-26a in mice exacerbates high-fat diet-induced ER stress, lipid accumulation, inflammation and hepatic steatosis. Conclusions Our findings suggest ER stress-induced miR-26a up-regulation as a regulator for hepatic ER stress resolution, and highlight the ER stress/miR-26a/eukaryotic initiation factor 2α cascade as a promising therapeutic strategy for NAFLD.

Significance Cure of autoimmune type 1 diabetes (T1D) requires both reversal of autoimmunity and regeneration or resupply of insulin-producing β cells. We have observed that combination therapy with induction of haploidentical mixed chimerism and administration of gastrin and epidermal growth factor (EGF) cures firmly established T1D. The predominant source of β cell regeneration in mice comes from reactivation of dysfunctional insulinlo β cells and transdifferentiation of α cells. These studies have provided insights into β cell regeneration mechanisms in firmly established autoimmune T1D, in particular, reactivation of the insulinlo β cells after reversal of autoimmunity by induction of haploidentical mixed chimerism. These studies also provide a preclinical scientific basis for the feasibility of cure of long-standing T1D in humans., Type 1 diabetes (T1D) results from the autoimmune destruction of β cells, so cure of firmly established T1D requires both reversal of autoimmunity and restoration of β cells. It is known that β cell regeneration in nonautoimmune diabetic mice can come from differentiation of progenitors and/or transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune nonobese diabetic (NOD) mice remains unclear. Here, we show that, after reversal of autoimmunity by induction of haploidentical mixed chimerism, administration of gastrin plus epidermal growth factor augments β cell regeneration and normalizes blood glucose in the firmly established diabetic NOD mice. Using transgenic NOD mice with inducible lineage-tracing markers for insulin-producing β cells, Sox9+ ductal progenitors, Nestin+ mesenchymal stem cells, and glucagon-producing α cells, we have found that both reactivation of dysfunctional low-level insulin expression (insulinlo) β cells and neogenesis contribute to the regeneration, with the latter predominantly coming from transdifferentiation of α cells. These results indicate that, after reversal of autoimmunity, reactivation of β cells and transdifferentiation of α cells can provide sufficient new functional β cells to reach euglycemia in firmly established T1D.

The photophysical tuning is reported for a series of tetraphenylphosphonium (TPP) metal halide hybrids containing distinct metal halides, TPP2 MXn (MXn =SbCl5 , MnCl4 , ZnCl4 , ZnCl2 Br2 , ZnBr4 ), from efficient phosphorescence to ultralong afterglow. The afterglow properties of TPP+ cations could be suspended for the hybrids containing low band gap emissive metal halide species, such as SbCl52- and MnCl42- , but significantly enhanced for the hybrids containing wide band gap non-emissive ZnCl42- . Structural and photophysical studies reveal that the enhanced afterglow is attributed to stronger π-π stacking and intermolecular electronic coupling between TPP+ cations in TPP2 ZnCl4 than in the pristine organic ionic compound TPPCl. Moreover, the afterglow in TPP2 ZnX4 can be tuned by controlling the halide composition, with the change from Cl to Br resulting in a shorter afterglow due to the heavy atom effect.

Scintillation based X-ray detection has received great attention for its application in a wide range of areas from security to healthcare. Here, we report highly efficient X-ray scintillators with state-of-the-art performance based on an organic metal halide, ethylenebis-triphenylphosphonium manganese (II) bromide ((C38H34P2)MnBr4), which can be prepared using a facile solution growth method at room temperature to form inch sized single crystals. This zero-dimensional organic metal halide hybrid exhibits green emission peaked at 517 nm with a photoluminescence quantum efficiency of ~ 95%. Its X-ray scintillation properties are characterized with an excellent linear response to X-ray dose rate, a high light yield of ~ 80,000 photon MeV−1, and a low detection limit of 72.8 nGy s−1. X-ray imaging tests show that scintillators based on (C38H34P2)MnBr4 powders provide an excellent visualization tool for X-ray radiography, and high resolution flexible scintillators can be fabricated by blending (C38H34P2)MnBr4 powders with polydimethylsiloxane., Scintillation-based X-ray detection is promising for applications in various areas ranging from security to healthcare, and low-cost and eco-friendly scintillation materials would be beneficial. Here the authors report a facile solution growth of organic manganese halide for efficient X-ray scintillation.

The high surface-to-volume ratio of nanostructured materials is the key factor for excellent performance when applied to chemical sensors. In order to achieve this by a facile and low-cost fabrication strategy, buffered oxide etchant (BOE) treatment of a silicon (Si)-based sensor was proposed. An n+-n--n+ Si nanofilm structure was treated with a BOE, and palladium nanoparticles (PdNPs) were coated on the n-type Si channel surface via short-time electron beam evaporation to enable a highly sensitive and selective sensing of hydrogen (H2) gas. The BOE treatment effect on lightly doped n-type Si was investigated, and the surface morphology of the etched Si was analyzed. Furthermore, the H2 sensing characterization of PdNP-decorated Si devices with various BOE treatment times was systematically evaluated at room temperature. The results revealed that the surface of n-type Si is roughened by BOE treatment, which can further enhance the H2-sensing performance of Pd-decorated Si. The elaborate study on the BOE-post-treated Si H2 sensor showed that the performance enhancement was stable. The BOE treatment strategy was also applied to the nanopatterned Si sensors, which induced a clear performance enhancement for the H2 sensing.

Zero-dimensional (0D) organic metal halide hybrids, in which organic and metal halide ions cocrystallize to form neutral species, are a promising platform for the development of multifunctional crystalline materials. Herein we report the design, synthesis, and characterization of a ternary 0D organic metal halide hybrid, (HMTA)4 PbMn0.69 Sn0.31 Br8 , in which the organic cation N-benzylhexamethylenetetrammonium (HMTA+ , C13 H19 N4 + ) cocrystallizes with PbBr4 2- , MnBr4 2- , and SnBr4 2- . The wide band gap of the organic cation and distinct optical characteristics of the three metal bromide anions enabled the single-crystalline "host-guest" system to exhibit emissions from multiple "guest" metal halide species simultaneously. The combination of these emissions led to near-perfect white emission with a photoluminescence quantum efficiency of around 73 %. Owing to distinct excitations of the three metal halide species, warm- to cool-white emissions could be generated by controlling the excitation wavelength.

Tin halide perovskites and perovskite-related materials have emerged as promising lead-free hybrid materials for various op-toelectronic applications. While remarkable progress has been achieved in...

Scintillators are utilized for X-ray detection in many important fields ranging from homeland security to health care. Developing low-cost, high-performance scintillation materials to address the i...

Biodegradable magnesium alloys are promising candidates for use in biomedical applications. However, degradable particles (DPs) derived from Mg-based alloys have been observed in tissue in proximity to sites of implantation, which might result in unexpected effects. Although previous in vitro studies have found that macrophages can take up DPs, little is known about the potential phagocytic pathway and the mechanism that processes DPs in cells. Additionally, it is necessary to estimate the potential bioeffects of DPs on macrophages. Thus, in this study, DPs were generated from a Mg-2.1Nd-0.2Zn-0.5Zr alloy (JDBM) by an electrochemical method, and then macrophages were incubated with the DPs to reveal the potential impact. The results showed that the cell viability of macrophages decreased in a concentration-dependent manner in the presence of DPs due to effects of an apoptotic pathway. However, the DPs were phagocytosed into the cytoplasm of macrophages and further degraded in phagolysosomes, which comprised lysosomes and phagosomes, by heterophagy instead of autophagy. Furthermore, several pro-inflammatory cytokines in macrophages were upregulated by DPs through the induction of reactive oxygen species (ROS) production. To the best of our knowledge, this is the first study to show that DPs derived from a Mg-based alloy are consistently degraded in phagolysosomes after phagocytosis by macrophages via heterophagy, which results in an inflammatory response owing to ROS overproduction. Thus, our research has increased the knowledge of the metabolism of biodegradable Mg metal, which will contribute to an understanding of the health effects of biodegradable magnesium metal implants used for tissue repair. STATEMENT OF SIGNIFICANCE: Biomedical degradable Mg-based alloys have great promise in applied medicine. Although previous studies have found that macrophages can uptake degradable particles (DPs) in vitro and observed in the sites of implantation in vivoin vivo, few studies have been carried out on the potential bioeffects relationship between DPs and macrophages. In this study, we analyzed the bioeffects of DPs derived from a Mg-based alloy on the macrophages. We illustrated that the DPs were size-dependently engulfed by macrophages via heterophagy and further degraded in the phagolysosome rather than autophagosome. Furthermore, DPs were able to induce a slight inflammatory response in macrophages by inducing ROS production. Thus, our research enhances the knowledge of the interaction between DPs of Mg-based alloy and cells, and offers a new perspective regarding the use of biodegradable alloys.

Compared with the significant number of studies reporting altered abundance and function of drug transporters at the blood-brain barrier (BBB) in Alzheimer's disease (AD), the impact of AD on the abundance of intestinal drug transporters and the subsequent effects on oral drug absorption have received little attention. We have reported the altered abundance of some small intestinal drug transporters in a familial mouse model of AD; however, whether this leads to altered oral drug absorption is unknown. The current study examined plasma concentrations of caffeine and diazepam (markers for transcellular passive transport), digoxin (P-glycoprotein substrate), and valsartan (multidrug resistance-associated protein 2 substrate) following oral administration to 8-10 month old female wild-type (WT) and APPswe/PSEN1dE9 (APP/PS1) transgenic mice, a commonly used mouse model of familial AD. The plasma exposure of valsartan and digoxin was significantly (p < 0.05) lower in APP/PS1 animals compared with WT mice, whereas the plasma concentrations of the passive transcellular markers caffeine and diazepam did not significantly differ between the two genotypes. To assess whether the reduced oral absorption of valsartan and digoxin was due to decreased intestinal transport, the ex vivo transport of the previously mentioned drugs and mannitol (a marker of paracellular transport) across the jejunum of WT and APP/PS1 mice was assessed over 120 min. In line with the in vivo absorption studies, the permeability of caffeine and diazepam did not significantly differ between WT and APP/PS1 mice. The permeability of 3H-digoxin through the APP/PS1 mouse jejunum was lower than that measured through the WT jejunum; the average amount (relative to dose applied) permeating the tissue over 120 min was 0.22 ± 0.11% (mean ± SD) for the APP/PS1 jejunum and 0.85 ± 0.3% for the WT jejunum. A 1.9-fold reduction in the average amount of valsartan permeating the jejunum of APP/PS1 mice relative to that of WT mice was also detected. Although no apparent morphological alterations were observed in the jejunal tissue of APP/PS1 mice, the permeability of 14C-mannitol across the jejunum from APP/PS1 mice was lower than that across the WT jejunum (Papp= 10.7 ± 3.7 × 10-6 and 6.0 ± 3.4 × 10-6 cm/s, respectively), suggesting tightened paracellular junctions in APP/PS1 mice. These studies are the first to demonstrate, in APP/PS1 mice, reduced intestinal permeability and the absorption of drugs commonly prescribed to people with AD for their comorbidities. If these findings translate to people with AD, then modified dosing regimens may be necessary for selected drugs to ensure that their plasma concentrations remain in the effective range.

Despite the high profile of aconine in WuTou injection, there has been no preparative technology or structural studies of its salt as the pharmaceutical product. The lack of any halide salt forms is surprising as aconine contains a tertiary nitrogen atom. In this work, aconine was prepared from the degradation of aconitine in Aconiti kusnezoffii radix (CaoWu). A green chemistry technique was applied to enrich the lipophilic-poor aconine. Reaction of aconine with hydrochloride acid resulted in protonation of the nitrogen atom and gave a novel salt form (C25H42NO9 +·Cl−·H2O; aconine hydrochloride monohydrate, AHM), whose cation in the crystal structure was elucidated based on extensive spectroscopic and X-ray crystallographic analyses. The AHM crystal had a Z′ = 3 structure with three independent cation–anion pairs, with profound conformational differences among the aconine cations. The central framework of each aconine cation was compared with that of previously reported aconitine, proving that protonation of the nitrogen atom induced the structure rearrangement. In the crystal of AHM, aconine cations, chloride anions and water molecules interacted through inter-species O—H...Cl and O—H...O hydrogen bonds; this complex hydrogen-bonding network stabilizes the supramolecular structure. The seriously disordered solvent molecules were treated using the PLATON SQUEEZE procedure [Spek (2015). Acta Cryst. C71, 9–18] and their atoms were therefore omitted from the refinement. Bioactivity studies indicated that AHM promoted in vitro proliferative activities of RAW264.7 cells. Molecular docking suggested AHM could target cardiotoxic protein through the hydrogen-bonding interactions. The structural confirmation of AHM offers a rational approach for improving the pharmaceutical technology of WuTou injection.

Bulk assemblies of zero-dimensional (0D) metal halides with exceptional structural versatility have enabled the development of a number of highly efficient emitters with tunable photophysical prope...

Brain levels of docosahexaenoic acid (DHA), an essential cognitively beneficial fatty acid, are reduced in Alzheimer's disease (AD). We have demonstrated in an AD mouse model that this is associated with reduced blood-brain barrier (BBB) transport of DHA and lower expression of the key DHA-trafficking protein, fatty acid-binding protein 5 (FABP5). This study focused on assessing the impact of activating peroxisome proliferator-activated receptor (PPAR) isoforms on FABP5 expression and function at the BBB. Using immortalized human brain endothelial (hCMEC/D3) cells, a 72 h treatment with the PPARα agonist clofibrate (100 μM), and PPARβ/δ agonists GW0742 (1 μM) and GW501506 (0.5 μM), did not affect FABP5 protein expression. In contrast, the PPARγ agonists rosiglitazone (5 μM), pioglitazone (25 μM), and troglitazone (1 μM) increased FABP5 protein expression by 1.15-, 1.18-, and 1.24-fold in hCMEC/D3 cells, respectively, with rosiglitazone and pioglitazone also increasing mRNA expression of FABP5. In line with an increase in FABP5 expression, pioglitazone increased 14C-DHA uptake into hCMEC/D3 cells 1.20- to 1.33-fold over a 2 min period, and this was not associated with increased expression of membrane transporters involved in DHA uptake. Furthermore, treating male C57BL/6J mice with pioglitazone (40 mg/kg/day for 7 days) led to a 1.79-fold increase in BBB transport of 14C-DHA over 1 min, using an in situ transcardiac perfusion technique, which was associated with a 1.82-fold increase in brain microvascular FABP5 protein expression. Overall, this study demonstrated that PPARγ can regulate FABP5 at the BBB and facilitate DHA transport across the BBB, important in restoring brain levels of DHA in AD.

Immunoglobulin A (IgA) is the most abundant antibody isotype in the mucosal immune system. Structurally, IgA in the mucosal surface is a polymeric structure, while serum IgA is monomeric. Secretory IgA (sIgA) is one of the polymeric IgAs composed of dimeric IgA, J chain, and secretory component (SC). Most of sIgAs were generated by gut and have effects in situ. Besides the function of “immune exclusion,” a nonspecific immune role, recent studies found it also played an important role in the specific immunity and immunoregulation. Thanks to the critical role of sIgA during the mucosal immune system homeostasis between commensal microorganisms and pathogens; it has been an important field exploring the relationship between sIgA and commensal microorganisms.

Surface passivation of metal halide perovskite thin films has proved to be critical for efficient and stable perovskite solar cells (PSCs), i.e. suppressing charge recombination at the interfaces between perovskite and charge transport layers for high device efficiency and preventing the penetration of degrading agents into the perovskite layer for high device stability. Here, we report the use of a new class of materials, phosphonium halide salts, i.e. triphenyl(9-ethyl-9H-carbazol-3-yl)-phosphonium bromide (TCPBr) and iodide (TCPI), as surface passivation agents for efficient and stable PSCs. Suppressed nonradiative recombination and enhanced interfacial hole extraction, enabled by this facile phosphonium halide passivation, resulted in PSCs with power conversion efficiencies (PCEs) of >20.1% (∼18.5% for pristine MAPbI3 devices). Phosphonium halide passivation also reduced the hysteresis index from 11.2% (pristine device) to 5.4% (TCPBr passivated device). Moreover, the hydrophobic phosphonium halide passivation layers significantly suppressed moisture penetration and ion migration, greatly enhancing the device stability. It was found that unencapsulated solar cells based on TCPBr treated MAPbI3 thin layers retained more than 90% of the initial PCEs after more than 1000 hours storage under ambient conditions. Our work established the potential of phosphonium-based materials for surface passivation of metal halide perovskites, providing a new route towards efficient and stable perovskite optoelectronic devices.

To inhibit hIAPP aggregation and reduce toxicity of its oligomers are one of the potential strategies for the treatment of Type 2 diabetes (T2D). It has been reported that there is an effective inhibitory effect on hIAPP aggregation by five natural flavonoids, including Genistein, Rutin, Quercetin, Epigallocatechin gallate (EGCG), and Silibinin, which are widely found in our daily food. However, the detailed mechanisms to inhibit hIAPP aggregation remain unclear. Here, we explore the mechanisms of the five flavonoids against hIAPP aggregation by molecular docking and molecular dynamics simulations. We show that these flavonoids can disaggregate Chain A and Chain B of hIAPP to reduce the extended conformation by binding with two regions of hIAPP, Leu12–Ala13–Asn14 and Asn31–Val32–Gly33–Ser34–Asn35, with the inhibitory ability of Genistein > Rutin > Quercetin > EGCG > Silibinin. These five compounds exhibit a common mechanism for disaggregation of the hIAPP pentamer; that is, they loosen the two nearest peptide chains to potentially destroy the hIAPP oligomer. Mutations of eight key residues remarkably affected by the flavonoids indicate that the secondary structures of the hIAPP pentamer change from β-sheet to be random coil, thereby to destroy its structural stability; moreover, the 28th (Ser), 12th (Leu) and 32nd (Val) amino acids exhibit significant effects on structural stability of the hIAPP pentamer, providing an important hint that these amino acids can be considered as potential targets for design of new candidate inhibitors against hIAPP oligomers. This work is beneficial to understanding of mechanism of these inhibits against hIAPP aggregation and will facilitate screening, modification, and design of new inhibitors.

An incubation experiment with equivalent N rates was conducted for 56 days using a typical black soil amended with chemical fertilizer with or without straw amendment using a 15N cross-labeling technique. Compared with the chemical fertilizer treatment (15NCF), chemical fertilizer combined with straw treatment (CF + S) showed a significantly higher (P

As low-dimensional lead-free hybrids with higher stability and lower toxicity than those of three-dimensional lead perovskites, organic antimony(III) halides show great application potential in opt-electronic field owing to diverse topologies along with exceptional optical properties. We report herein an antimony(III) hybrid (MePPh3 )2 SbCl5 with a zero-dimensional (0D) structure, which exhibits brilliant orange emission peaked at 593 nm with near-unity photoluminescent quantum yield (99.4 %). The characterization of photophysical properties demonstrates that the broadband emission with a microsecond lifetime (3.24 μs) arises from self-trapped emission (STE). Electrically driven organic light-emitting diodes (OLEDs) based on neat and doped films of (MePPh3 )2 SbCl5 were fabricated. The doped devices show significant improvement in comparison to non-doped OLEDs. Owing to the much improved surface morphology and balanced carrier transport in light-emitting layers of doped devices, the peak luminance, current efficiency (CE) and external quantum efficiency (EQE) are boosted from 82 cd m-2 to 3500 cd m-2 , 1.1 cd A-1 to 6.8 cd A-1 , and 0.7 % to 3.1 % relative to non-doped devices, respectively.

In this work, by using two kinds of viologen ligands three POM-based Compounds were obtained under hydrothermal conditions, namely [AgI (bmypd)0.5 (β-Mo8 O26 )0.5 ] (1) (bmypd ⋅ 2Cl=1,1'-[Biphenyl-4,4'-bis(methylene)]bis(4,4'-bipyridyinium)dichloride), [AgI2 (bypy)4 (HSiW12 O40 )2 ] ⋅ 14H2 O (2) and [AgI (bypy)(γ-Mo8 O26 )0.5 ] (3) (bypy⋅Cl=1-Benzyl-4,4'-bipyridyinium chloride). The structures were characterized by Fourier transform infrared spectroscopy (FT-IR), Powder X-ray diffraction (PXRD), X-ray photoelectron spectroscopy (XPS) and single crystal X-ray diffraction. Compounds 1-3 show excellent photochromic ability with fast photoresponse under the irradiation of ultraviolet light with different degrees of color changes. So compounds 1-3 can be used as visible ultraviolet detectors. Compounds 1-3 also possess photoluminescence properties with fast and excellent fluorescence quenching effect. Compounds 1-3 also can be used as inkless and erasable printing materials with suspensions of 1-3 applied to filter paper. Compounds 1-3 can also produce color changes in amine vapor environment, especially in an NH3 atmosphere. Compounds 1-3 can be used as organic amine detectors.

The pandemic of COVID-19 by SARS-CoV-2 has become a global disaster. However, we still don’t know how specific SARS-CoV-2-encoded proteins contribute to viral pathogenicity. We found that SARS-CoV-2-encoded membrane glycoprotein M could induce caspase-dependent apoptosis via interacting with PDK1 and inhibiting the activation of PDK1-PKB/Akt signaling. Our investigation further revealed that SARS-CoV-2-encoded nucleocapsid protein N could specifically enhance the M-induced apoptosis via interacting with both M and PDK1, therefore strengthening M-mediated attenuation of PDK1-PKB/Akt interaction. Furthermore, when the M-N interaction was disrupted via certain rationally designed peptides, the PDK1-PKB/Akt signaling was restored, and the boosting activity of N on the M-triggered apoptosis was abolished. Overall, our findings uncovered a novel mechanism by which SARS-CoV-2-encoded M triggers apoptosis with the assistance of N, which expands our understanding of the two key proteins of SARS-CoV-2 and sheds light on the pathogenicity of this life-threatening virus.

Background: Human tauopathies including Alzheimer's disease (AD) are characterized by alterations in the post-translational modification (PTM) pattern of Tau, which parallel the formation of insoluble Tau aggregates, neuronal dysfunction and degeneration. While PTMs on aggregated Tau have been studied in detail, much less is known about the modification patterns of soluble Tau. Furthermore, PTMs other than phosphorylation have only come into focus recently and are still understudied. Soluble Tau species are likely responsible for the spreading of pathology during disease progression and are currently being investigated as targets for immunotherapies. A better understanding of their biochemical properties is thus of high importance. Methods: We used a mass spectrometry approach to characterize Tau PTMs on a detergent-soluble fraction of human AD and control brain tissue, which led to the discovery of novel lysine methylation events. We developed specific antibodies against Tau methylated at these sites and biochemically characterized methylated Tau species in extracts from human brain, the rTg4510 mouse model and in hiPSC-derived neurons. Results: Our study demonstrates that methylated Tau levels increase with Tau pathology stage in human AD samples as well as in a mouse model of Tauopathy. Methylated Tau is enriched in soluble brain extracts and is not associated with hyperphosphorylated, high molecular weight Tau species. We also show that in hiPSC-derived neurons and mouse brain, methylated Tau preferentially localizes to the cell soma and nuclear fractions and is absent from neurites. Knock down and inhibitor studies supported by proteomics data led to the identification of SETD7 as a novel lysine methyltransferase for Tau. SETD7 specifically methylates Tau at K132, an event that facilitates subsequent methylation at K130. Conclusions: Our findings indicate that methylated Tau has a specific somatic and nuclear localization, suggesting that the methylation of soluble Tau species may provide a signal for their translocation to different subcellular compartments. Since the mislocalization and depletion of Tau from axons is associated with tauopathies, our findings may shed light onto this disease-associated phenomenon. Funding: Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinson’s Research

A maize pot experiment was conducted to compare the difference of N distribution between bulk and rhizospheric soil after chemical fertilizer with or without soil straw amendment at an equivalent N rate using a 15N cross-labeling technique. Soil N pools, maize N and their 15N abundances were determined during maize growth. The urea plus straw treatment significantly (p &lt, 0.05) increased the recovery of urea N in soil and 26.0% of straw N was assimilated by maize. Compared with urea treatment in bulk soil, urea plus straw treatment significantly (p &lt, 0.05) increased the concentration and percentage of applied N as dissolved organic N (DON) and microbial biomass N (MBN) from milk stage to maturity, increased those as particulate organic N (PON) and mineral associated total N (MTN) throughout maize growth and decreased those as inorganic N (Inorg-N) from the eighth leaf to the silking stage. Compared with bulk soil, rhizospheric soil significantly (p &lt, 0.05) decreased the concentration and percentage of applied N as PON and increased those as Inorg-N and MTN in both applied N treatments from the silking stage, and significantly (p &lt, 0.05) decreased the concentration and percentage of applied N as microbial biomass N (MBN) in the urea plus straw treatment. Overall, straw N was an important N source and combined application of chemical fertilizer with straw increased soil fertility, with the rhizosphere regulating the transformation and supply of different N sources in the soil–crop system.

Organometal halide perovskite materials, in particular colloidal perovskite nanocrystals (NCs), have been investigated extensively as next-generation light-emitting materials. However, producing highly efficient and stable perovskite thin films from colloidal NCs is not trivial, as dissociation of surfactants often occurs during the thin-film formation. Here, we demonstrate a facile solution-processing approach to prepare perovskite nanocomposite thin films by using phosphonium as the capping ligand for methylammonium lead bromide (MAPbBr

Bovine lactoferrin N-lobe plays an important key in the nonimmunological defense system. In this work, the most suitable promoter Pveg was selected and the fragment coding bovine lactoferrin N-lobe was optimized according to codon bias of Bacillus. The recombinant plasmid pMA0911-Pveg-mBLF-N was introduced into Baicillus subtilis 168 to create B. subtilis/pMA0911-Pveg-mBLF-N. The bovine lactoferrin N-lobe was highly expressed at 28 °C for 15 h. Its purified protein was obtained with 16.5 mg/L and a purity of 93.6% using ammonium sulfate precipitation, Ni-NTA, and molecular exclusion. About 200 ng/mL purified bovine lactoferrin N-lobe completely inhibited cell-growth of Escherichia coli JM109 (DE3), 70.3% of Pseudomonas aeruginosa CGMCC 1.6740, and 41.5% of Staphylococcus aureus CGMCC 1.282. To our knowledge, this is the first report about active expression, purification, and characterization of bovine lactoferrin N-lobe in safe bacterium B. subtilis, which opens an available application way in the biomedical and food industries.

Blueberry is one of the richest phenolic sources, providing health benefits. To study blueberry phenolic biosynthesis, we investigated phenolics and proteomics at three typical fruit maturation phases. Multiple isoforms of enzymes and multiple members of transcription factors involved in phenolic biosynthesis were divergent and differently regulated. Regulation of some proteins resulted in change of phenolic content. During fruit maturation, down-regulation of VcOMT (CUFF.177.1) and VcLAR2 (CUFF.16780.1) was associated with decreases of ferulic acid and catechin, respectively; Up-regulation of VcFLS (CUFF.41155.1), and VcF3'5'H (CUFF.51711.1) and VcF3'5'H (gene.g10884.t1.1) likely drove increases of their products (quercetin and myricetin); Up-regulation of VcUFGALT (CUFF.20951.1) and VcUFGT73 (4333_g.1) and down-regulation of VcU5GT (CUFF.51258.1) were correlated to accumulation of anthocyanins with 3-glucoside/galactoside. Additionally, four TFs, VcAPRR2 (CUFF.24826.1), VcbHLH3 (CUFF.37765.1), VcWD (CUFF.28282.2) and VcWD (CUFF.28273.1) were probably related to regulation of anthocyanin biosynthesis. These proteins were potential targets for genetic improvement in a breeding program.

The combination of controlled release technology and targeted drug delivery has become a promising strategy for cancer therapy. In this study, cell-nanoparticle hybrid vector was constructed using mesenchymal stem cells as the targeting cellular carrier and biotinylated chitosan polymer nanoparticles as the drug depot. Drug-loaded nanoparticles (hydrodynamic size =377.0 ± 14.6 nm and zeta potential = 9.6 ± 1.9 mV) were prepared by encapsulating hydrophobic model drug curcumin into biotinylated chitosan polymer. The biotin-modified nanoparticles were anchored on biotinylated mesenchymal stem cells surface by biotin-avidin binding, achieving an upload of 54.73 ± 3.95 pg/cell. The anchorage of nanoparticles on mesenchymal stem cells had no effect on their viability and homing property. Biotin-avidin binding lasted over 48 h, which could be sufficient for cell-directed tumor-tropic delivery. The in vitro and in vivo anti-tumor results advocate that cell-nanoparticle hybrid vector could prove beneficial in pulmonary melanoma metastasis therapy.

An undescribed isoprenylated flavonol racemate, nigranol C, with an unprecedented 7/6/6 ring system, was isolated from the twigs of Morus nigra L. The structure was assigned through a comprehensive analysis of HRMS, IR, and NMR data. Chiral separation of nigranol C was successfully carried out to yield a pair of enantiomers, nigranol C-a and nigranol C-b, whose absolute configurations were determined by ECD calculation. A plausible biogenetic pathway for nigranol C was proposed. A previously isolated sanggenon-type flavonone racemate, nigragenon E, was also well resolved by chiral HPLC to offer another pair of enantiomers, nigragenon E-a and nigragenon E-b, whose stereo configurations were determined by ECD data. All of the isolated compounds showed prominent α-glucosidase inhibitory activities with IC50 values ranging from 9.79 to 30.21 μM, while only the sanggenon-type flavonones exhibited tyrosinase inhibitory effects comparable to that of the positive control, kojic acid, the IC50 value of which was 27.14 μM. In addition, it was found that the stereo configurations of these compounds seemed to play a negligible role in their inhibitory activities towards the two enzymes.