A dToF Ranging Sensor with Accurate Photon Detector Measurements for LiDAR Applications.

Direct time-of-flight (dToF) ranging sensors based on single-photon avalanche diodes (SPADs) have been used as a prominent depth-sensing devices. Time-to-digital converters (TDCs) and histogram builders have become the standard for dToF sensors. However, one of the main current issues is the bin width of the histogram, which limits the accuracy of depth without TDC architecture modifications. SPAD-based light detection and ranging (LiDAR) systems require new methods to overcome their inherent drawbacks for accurate 3D ranging. In this work, we report an optimal matched filter to process the raw data of the histogram to obtain high-accuracy depth. This method is performed by feeding the raw data of the histogram into the different matched filters and using the Center-of-Mass (CoM) algorithm for depth extraction. Comparing the measurement results of different matched filters, the filter with the highest depth accuracy can be obtained. Finally, we implemented a dToF system-on-chip (SoC) ranging sensor. The sensor is made of a configurable array of 16 × 16 SPADs, a 940 nm vertical-cavity surface-emitting laser (VCSEL), an integrated VCSEL driver, and an embedded microcontroller unit (MCU) core to implement the best matched filter. To achieve suitably high reliability and low cost, the above-mentioned features are all packaged into one module for ranging. The system resulted in a precision of better than 5 mm within 6 m with 80% reflectance of the target, and had a precision better than 8 mm at a distance within 4 m with 18% reflectance of the target.

Effects of macrophages on the proliferation and cardiac differentiation of human induced pluripotent stem cells.

BACKGROUND: Macrophage phenotypes switch from proinflammatory (M1) to anti-inflammatory (M2) following myocardial injury. Implanted stem cells (e.g., induced pluripotent stem cells (iPSCs)) for cardiomyogenesis will inevitably contact the inflammatory environment at the myocardial infarction site. To understand how the macrophages affect the behavior of iPSCs, therefore, improve the therapeutic efficacy, we generated three macrophage subtypes and assessed their effects on the proliferation, cardiac differentiation, and maturation of iPSCs. METHODS: M0, M1, and M2 macrophages were polarized using cytokines, and their properties were confirmed by the expression of specific markers using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence. The effects of macrophages on iPSCs were studied using Transwell co-culture models. The proliferative ability of iPSCs was investigated by cell counting and CCK-8 assays. The cardiac differentiation ability of iPSCs was determined by the cardiomyocyte (CM) yield. The maturation of CM was analyzed by the expression of cardiac-specific genes using RT-qPCR, the sarcomere organization using immunofluorescence, and the mitochondrial function using oxidative respiration analysis. RESULTS: The data showed that the co-culture of iPSCs with M0, M1, or M2 macrophages significantly decreased iPSCs' proliferative ability. M2 macrophages did not affect the CM yield during the cardiac differentiation of iPSCs. Still, they promoted the maturation of CM by improving sarcomeric structures, increasing contractile- and ion transport-associated gene expression, and enhancing mitochondrial respiration. M0 macrophages did not significantly affect the cardiomyogenesis ability of iPSCs during co-culture. In contrast, co-culture with M1 macrophages significantly reduced the cardiac differentiation and maturation of iPSCs. CONCLUSIONS: M1- or M2-polarized macrophages play critical roles in the proliferation, cardiac differentiation, and maturation of iPSCs, providing knowledge to improve the outcomes of stem cell regeneration therapy. Video abstract.

[Exploration and Thinking on Fine Management of Cost Accounting of Medical Consumables].

With the gradual advancement of The Reform Plan to Control High-value Medical Consumables published by the State Council, the reform policies such as purchase with quantity, charging consumables" zero bonus" were born, the operating pressure of medical institutions on medical consumables increased sharply, and the fine cost accounting management demands were improving. Due to the manage features of medical consumables, this will lead to the inaccurate and cross-cycle of cost accounting. In order to achieve the refined cost accounting management, the related business system and process adjustment are studied.

Copper(i)-polymers and their photoluminescence thermochromism properties.

Under hydro(solvo)thermal conditions, four organic bidentate bridging N,N'-donor ligands 1,3-bis(2-methylimidazol-1-yl)propane (L1), 4,4'-di(1H-imidazol-1-yl)-1,1'-biphenyl (L2), 1,2-bis(2-methyl-1H-imidazol-1-ylmethyl)benzene (L3) and 5,6,7,8-tetrahydroquinoxaline (L4) were employed to react with CuBr/CuI, generating four 2-D layered copper(i)-polymer coordination polymer materials [Cu2Br2(L1)] 1, [CuI(L2)] 2, [CuI(L3)] 3 and [CuI(L4)0.5] 4. In 1-4, different Cu-X motifs are found: a cubic Cu4Br4 core in 1; a castellated Cu-I single chain in 2; a rhombic Cu2I2 core in 3; and a staircase-like Cu-I double chain in 4. The 2-D layer networks of 1-3 can all be simplified into a simple 44 topology (planar for 1 and 3; wave-like for 2), while the 2-D layer network of 4 has a 63 topology. The photoluminescence behaviors of 1-4 under a UV lamp suggest that 1 and 2 possess fluorescence thermochromism properties. Under the UV lamp, with the decrease in temperature, (i) 1 exhibits a yellow-to-red emission; (ii) 2 exhibits a yellow-to-green emission; (iii) 3 always emits green light; and (iv) 4 never emits light. These are further confirmed by their emission spectra. From 297 K to 77 K, the emission of 1 exhibits a large red shift from 561 nm to 623 nm; the emission of 2 exhibits a large blue shift from 571 nm to 515 nm; only a minor red shift is observed for the emission of 3; and no peaks appear in the emission spectra of 4. The crystal data of 1 and 2 at different temperatures have been collected for revealing the origination of their fluorescence thermochromism properties. Based on the above investigations, the effect of the rigidity/flexibility of the organic ligand on the fluorescence thermochromism properties of copper(i)-polymer coordination polymer materials is discussed. The quantum yields at 297 K and the photoluminescence lifetimes at 297 K and 77 K for 1-3 were also measured for better understanding their photoluminescence properties.

A Series of Compounds Based on [P2W18O62]6- and Transition Metal Mixed Organic Ligand Complexes with High Catalytic Properties for Styrene Epoxidation.

Seven compounds based on [P2W18O62]6- ({P2W18}) were successfully prepared and carefully characterized. [HC5H5N][Cu(2,2'-bpy)2]2[HP2W18O62]·2H2O (bpy = bipyridine) (1) is constructed from {P2W18} bridged by [Cu(2,2'-bpy)2]2+. [HC5H5N][Zn(2,2'-bpy)2]2[HP2W18O62]·4H2O (1a) is isostructural and isomorphous with compound 1. [Cu4(2,2'-bpy)3(nic)3(OH)2(H2O)][H3P2W18O62]·0.5H2O (nic = nicotinic acid) (2) is formed by {P2W18} and tetracopper transition metal mixed organic ligand complexes (TMMCs). [Cu2(2,2'-bpy)2(C2O4)]3[P2W18O62]·3H2O (3) is made up of {P2W18} and bicopper TMMCs, [Cu6(2,2'-bpy)6(OH)6][P2W18O62]·2H2O (4) is built up from {P2W18}, and hexacopper complexes of 2,2'-bpy and hydroxyls. [Cu(2,2'-bpy)(hnic)0.5][Cu3(2,2'-bpy)3(hnic)2(H2O)2][H3P2W18O62] (hnic = hydroxyl nicotinic acid) (5a) contains two different TMMCs. In addition, compound 5a is the first example of a compound that contains Cu-π interactions. [Cu2(2,2'-bpy)2(hnic)][H4P2W18O62]· xH2O ( x ≈ 50) (5b) is based on {P2W18} and [Cu2(2,2'-bpy)2(hnic)]2+. We discuss the mechanisms for the formations of these compounds. All the catalytic performances of the compounds for styrene epoxidation to styrene oxide are high.

Heterodimerization of p45-p75 modulates p75 signaling: structural basis and mechanism of action.

The p75 neurotrophin receptor, a member of the tumor necrosis factor receptor superfamily, is required as a co-receptor for the Nogo receptor (NgR) to mediate the activity of myelin-associated inhibitors such as Nogo, MAG, and OMgp. p45/NRH2/PLAIDD is a p75 homologue and contains a death domain (DD). Here we report that p45 markedly interferes with the function of p75 as a co-receptor for NgR. P45 forms heterodimers with p75 and thereby blocks RhoA activation and inhibition of neurite outgrowth induced by myelin-associated inhibitors. p45 binds p75 through both its transmembrane (TM) domain and DD. To understand the underlying mechanisms, we have determined the three-dimensional NMR solution structure of the intracellular domain of p45 and characterized its interaction with p75. We have identified the residues involved in such interaction by NMR and co-immunoprecipitation. The DD of p45 binds the DD of p75 by electrostatic interactions. In addition, previous reports suggested that Cys257 in the p75 TM domain is required for signaling. We found that the interaction of the cysteine 58 of p45 with the cysteine 257 of p75 within the TM domain is necessary for p45-p75 heterodimerization. These results suggest a mechanism involving both the TM domain and the DD of p45 to regulate p75-mediated signaling.

The microparticulate inks for bioprinting applications.

Three-dimensional (3D) bioprinting has emerged as a groundbreaking technology for fabricating intricate and functional tissue constructs. Central to this technology are the bioinks, which provide structural support and mimic the extracellular environment, which is crucial for cellular executive function. This review summarizes the latest developments in microparticulate inks for 3D bioprinting and presents their inherent challenges. We categorize micro-particulate materials, including polymeric microparticles, tissue-derived microparticles, and bioactive inorganic microparticles, and introduce the microparticle ink formulations, including granular microparticles inks consisting of densely packed microparticles and composite microparticle inks comprising microparticles and interstitial matrix. The formulations of these microparticle inks are also delved into highlighting their capabilities as modular entities in 3D bioprinting. Finally, existing challenges and prospective research trajectories for advancing the design of microparticle inks for bioprinting are discussed.

Dexmedetomidine protects against sepsis-induced lung injury through autophagy and Smad2/3 signaling pathway.

Objectives: Dexmedetomidine (Dex) is a potent α2-adrenergic receptor(α2-AR) agonist that has been shown to protect against sepsis-induced lung injury, however, the underlying mechanisms of this protection are not fully understood. Autophagy and the Smad2/3 signaling pathway play important roles in sepsis-induced lung injury, but the relationship between Dex and Smad2/3 is not clear. This study aimed to investigate the role of autophagy and the Smad2/3 signaling pathway in Dex-mediated treatment of sepsis-induced lung injury. Sepsis was performed using cecal ligation and puncture (CLP) in C57BL/6J mice. Materials and Methods: Mice were randomly assigned to four groups (n=6 per group): sham, CLP, CLP-Dex, and CLP-Dex-YOH, Yohimbine hydrochloride (YOH) is an α2-AR blocker. The cecum was carefully separated to avoid blood vessel damage and was identified and punctured twice with an 18-gauge needle. The pathological changes, inflammatory factor levels, oxidative stress, autophagy, Smad2/3 signaling pathway-related protein levels in lung tissues, and the activity of superoxide dismutase (SOD) and malonaldehyde (MDA) in the serum were measured. Results: CLP-induced lung injury was reflected by increased levels of inflammatory cytokines, apoptosis, and oxidative stress, along with an increase in the expression of autophagy and Smad2/3 signaling pathway-related proteins. Dex could reverse these changes and confer a protective effect on the lung during sepsis. However, the administration of YOH significantly reduced the positive effects of Dex in mice with sepsis. Conclusion: Dex exerts its beneficial effects against sepsis-induced lung injury through the regulation of autophagy and the Smad2/3 signaling pathway.

HIV-1 reduces Abeta-degrading enzymatic activities in primary human mononuclear phagocytes.

The advent and wide introduction of antiretroviral therapy has greatly improved the survival and longevity of HIV-infected patients. Unfortunately, despite antiretroviral therapy treatment, these patients are still afflicted with many complications including cognitive dysfunction. There is a growing body of reports indicating accelerated deposition of amyloid plaques, which are composed of amyloid-ß peptide (Aß), in HIV-infected brains, though how HIV viral infection precipitates Aß accumulation is poorly understood. It is suggested that viral infection leads to increased production and impaired degradation of Aß. Mononuclear phagocytes (macrophages and microglia) that are productively infected by HIV in brains play a pivotal role in Aß degradation through the expression and execution of two endopeptidases, neprilysin (NEP) and insulin-degrading enzyme. In this study, we report that NEP has the dominant endopeptidase activity toward Aß in macrophages. Further, we demonstrate that monomeric Aß degradation by primary cultured macrophages and microglia was significantly impaired by HIV infection. This was accompanied with great reduction of NEP endopeptidase activity, which might be due to the diminished transport of NEP to the cell surface and intracellular accumulation at the endoplasmic reticulum and lysosomes. Therefore, these data suggest that malfunction of NEP in infected macrophages may contribute to acceleration of ß amyloidosis in HIV-inflicted brains, and modulation of macrophages may be a potential preventative target of Aß-related cognitive disorders in HIV-affected patients.

2-Ketogluconic acid production by Klebsiella pneumoniae CGMCC 1.6366.

Klebsiella pneumoniae CGMCC 1.6366 is a bacterium isolated for 1,3-propanediol or 2,3-butanediol production previously. K. pneumoniae ΔbudA, a 2,3-butanediol synthesis pathway truncated mutant with the gene deletion of budA which encodes alpha-acetolactate decarboxylase, was found to execrate an unknown chemical at a high titer when grown in the broth using glucose as carbon source. Later this chemical was identified to be 2-ketogluconic acid, which was formed through the glucose oxidation pathway in K. pneumoniae. It was found that 2-ketogluconic can also be produced by the wild strain. The fermentation studies showed that the production of this metabolite is strictly pH dependent, when the fermenting broth was maintained at pH 6-7, the main metabolite produced by K. pneumoniae CGMCC 1.6366 was 2,3-butanediol, or some organic acids in the budA mutated strain. However, if the cells were fermented at pH 4.7, 2-ketogluconic acid was formed, and the secretion of all other organic acids or 2,3-butanediol were limited. In the 5L bioreactors, a final level of 38.2 and 30.2 g/L 2-ketogluconic acid were accumulated by the wild type and the budA mutant K. pneumoniae, respectively, in 26 and 56 h; and the conversion ratios of glucose to 2-ketogluconic acid reached 0.86 and 0.91 mol/mol for the wild and the budA mutant, respectively.

Xanthine oxidase, a therapeutic target of realgar for non-small cell lung cancer.

Background: The effects of realgar against non-small cell lung cancer (NSCLC) have been massively studied, but the direct therapeutic targets of realgar remain unclear. This study aimed to identify the molecular targets of realgar against NSCLC and explore their therapeutic mechanisms based on a network pharmacology approach and experimental validations. Methods: The BATMAN-TCM and Digsee databases were used to predict realgar targets and NSCLC-related genes, respectively. A protein-protein interaction network was constructed for each gene set, and the overlapping genes were identified as potential targets of realgar against NSCLC. The correlation between potential targets and NSCLC was analyzed using The Cancer Genome Atlas and International Cancer Genome Consortium databases, and the key target was validated by in-silico and in-vitro experiments. Results: Twenty-three overlapping genes, including xanthine oxidase (XO), were identified as potential targets of realgar against NSCLC. XO was selected as the key target for validation, as it was found to be upregulated in NSCLC tumor tissue, which correlated with poor overall survival. A possible interaction between realgar and XO was revealed by molecular docking which was further validated experimentally. Realgar treatment suppressed the activity of XO in NSCLC cells, as demonstrated by the unchanged XO protein levels. Finally, the mechanism of action of XO as a target against NSCLC through the cell-cell junction organization pathway was investigated. Conclusions: Overall, this study proposes a potential molecular mechanism illustrating that XO is a target of realgar against NSCLC and highlights the usefulness of XO as a therapeutic target for NSCLC.

Antibody-based binding domain fused to TCRγ chain facilitates T cell cytotoxicity for potent anti-tumor response.

Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated potent clinical efficacy in the treatment of hematopoietic malignancies. However, the application of CAR-T in solid tumors has been limited due in part to the expression of inhibitory molecules in the tumor microenvironment, leading to T-cell exhaustion. To overcome this limitation, we have developed a synthetic T-cell receptor (TCR) that targets programmed death-ligand 1 (PD-L1), a molecule that is widely expressed in various solid tumors and plays a pivotal role in T-cell exhaustion. Our novel TCR platform is based on antibody-based binding domain, which is typically a single-chain variable fragment (scFv), fused to the γδ TCRs (TCRγδ). We have utilized the T-cell receptor alpha constant (TRAC) locus editing approach to express cell surface scFv of anti-PD-L1, which is fused to the constant region of the TCRγ or TCRδ chain in activated T cells derived from peripheral blood mononuclear cells (PBMCs). Our results indicate that these reconfigured receptors, both γ-TCRγδ and δ-TCRγδ, have the capability to transduce signals, produce inflammatory cytokines, degranulate and exert tumor killing activity upon engagement with PD-L1 antigen in vitro. Additionally, we have also shown that γ-TCRγδ exerted superior efficacy than δ-TCRγδ in in vivo xenograft model.

A metal-organic framework with rich accessible nitrogen sites for rapid dye adsorption and highly efficient dehydrogenation of formic acid.

MOFs with adequate free nitrogen sites have potential applications in dye adsorption and formic acid dehydrogenation. Here, we successfully synthesized a novel 3-D MOF 1 ([(CH3)2NH2][Cd(L)DMA]·0.5DMA·1.5H2O) with a special two-fold interpenetrating framework through a simple solvothermal reaction between CdCl2·1.5H2O and a nitrogen-rich triangular tricarboxylate-based linker (H3L, 4,4',4''-s-triazine-2,4,6-tribenzoic acid). After removing the guest molecules of dimethylacetamide (DMA) and H2O, including the coordinated DMA from 1 by vacuum activation at 423 K, a compound named 1' with a formula of [(CH3)2NH2][Cd(L)] and a similar interpenetrating framework structure was obtained. In comparison with compound 1, the total void volume of 1' is nearly doubled, and thus may provide higher potential for the adsorption of other guest molecules. Notably, the pyridine N atoms located in the middle of the triangular tricarboxylate-based linker are not involved in the coordination with Cd2+, and are all uniformly dispersed throughout the whole framework of the 3-D MOFs. Due to its unique structural features, the 3-D MOF 1' could effectively adsorb the cationic dye MB+ for recycling purposes. The rapid adsorption rate (0.7 × 10-2 g mg-1 min-1) and the relatively high capacity (900 mg g-1) for MB+ demonstrate the potential of 1' in dye adsorption. In addition, 1' may also be used as an effective support to immobilize PdAu NPs via the double-solvent method. The resultant catalyst Pd0.8Au0.2/1' exhibits decent catalytic activity for the dehydrogenation of formic acid with a TOF value of 1854 h-1 at 333 K. The existence of a large void volume and accessible pyridine N atoms provide a suitable environment for achieving a high dispersion of PdAu NPs, thereby leading to the formation of a catalytically active and stable supported noble-metal NP catalyst for H2 generation from formic acid decomposition.

Actin interaction and regulation of cyclin-dependent kinase 5/p35 complex activity.

Cyclin-dependent kinase 5 (Cdk5) plays a critical role during neurodevelopment, synaptic plasticity, and neurodegeneration. Cdk5 activity depends on association with neuronal proteins p35 and p25, a proteolytic product of p35. Cdk5 regulates the actin cytoskeletal dynamics that are essential for neuronal migration, neuritic growth, and synaptogenesis. However, little is known about the interaction of actin and Cdk5 and its effect on neuronal Cdk5 activity. In a previous study, we observed that Cdk5/p35 activity is negatively correlated with co-immunoprecipitated F-actin (filamentous actin) amounts in the mouse brain, and suggested that F-actin inhibits the formation of the Cdk5/p35 complex [Journal of Neuroscience (2008) vol. 28, p. 14511]. The experiments reported here were undertaken to elucidate the relationship between actin and the formation of the Cdk5/p35 complex and its activity. Instead of an F-actin-mediated inhibition, we propose that G-actin (globular actin) in the F-actin preparations is responsible for inhibiting Cdk5/p35 and Cdk5/p25 kinase activity. We found that F-actin binds to p35 but not p25 or Cdk5. We have shown that G-actin binds directly to Cdk5 without disrupting the formation of the Cdk5/p35 or Cdk5/p25 complexes. G-actin potently suppressed Cdk5/p35 and Cdk5/p25 activity when either histone H1 or purified human tau protein were used as substrates, indicating a substrate-independent inhibitory effect of G-actin on Cdk5 activity. Finally, G-actin suppressed the activity of Cdk5 immunoprecipitated from wild type and p35-deficient mouse brain, suggesting that G-actin suppresses endogenous Cdk5 activity in a p35-independent manner. Together, these results suggest a novel mechanism of actin cytoskeletal regulation of Cdk5/p35 activity.

Tau-tubulin kinase 1 enhances prefibrillar tau aggregation and motor neuron degeneration in P301L FTDP-17 tau-mutant mice.

Tau-tubulin kinase-1 (TTBK1) phosphorylates microtubule-associated protein tau at specific serine/threonine residues found in paired helical filaments (PHFs), and its expression is up-regulated in the brain in Alzheimer disease, suggesting its role in tauopathy pathogenesis. To understand the effects of TTBK1 on tauopathy in vivo, we have developed bigenic mice overexpressing full-length TTBK1 and the P301L tau mutant. The bigenic mice show enhanced tau phosphorylation at multiple sites (AT8, 12E8, PHF-1, and pS422), tauC3-immunoreactive tau fragmentation, and accumulation of tau aggregates in cortical and hippocampal neurons at 12-13 mo of age. However, the phosphorylated tau aggregates were predominantly sarkosyl soluble and migrated in the light sucrose density fraction after discontinuous sucrose gradient ultracentrifugation, which suggests that they form small oligomers. The bigenic mice show significant locomotor dysfunction as determined by both rotorod and grip strength tests, as well as enhanced loss of motor neurons in the L4-L5 spinal cord. This neuronal dysfunction and degeneration was associated with increased levels of tau oligomers, cyclin-dependent protein kinase 5 activators p35 and p25, and pY216 phosphorylated glycogen synthase kinase 3-beta. These data suggest that TTBK1 up-regulation enhances tau phosphorylation and oligomerization, whose toxicity results in enhanced neurodegeneration and locomotor dysfunction in a tauopathy animal model.

Porous 3,4-di(3,5-dicarboxyphenyl)phthalate-based Cd2+ coordination polymer and its potential applications.

Porous coordination polymers with organic aminium as one of the guest species possess a potential application in dye adsorption and white-light material manufacture. Polycarboxylic acid with multiple COOH substituents tends to form this type of porous material (with metal ion). Here the solvothermal self-assembly between Cd2+ and a hexacarboxylic acid creates such a porous material [(CH3)2NH2]6[Cd3(L)2]·5DMF·3H2O (H6L = 3,4-di(3,5-dicarboxyphenyl)phthalic acid) 1. Total potential guest accessible void volume in 3-D 1 is found to be 4327 Å3. Based on its better porous structure and stability, the ability of 1 to adsorb organic dyes is investigated. It has been proved that (i) 1 can selectively adsorb cationic dyes as Azure A (AA+) and/or Methylene Blue (MB+), rather than neutral and anionic ones; (ii) the maximum adsorption capacity is 698.2 mg·g-1 for AA+ and 573.2 mg·g-1 for MB+, respectively; and (iii) to the adsorption of AA+, it can be recycled for at least five rounds. Also, it is utilized to fabricate the while-light emitting material. Based on the blue-light emission of 1, the trace Eu3+ and Tb3+ ions are introduced into the pores of 1 successfully, obtaining a white-light emitting material Eu3+/Tb3+@1 (CIE chromaticity coordinates: (0.33, 0.32)). Meanwhile, Eu3+/Tb3+@1 is found to be a potential fluorescence photochromic material, showing a yellow-white-blue light emission. According to these investigations, the relationship between material structure and its adsorption property for dyes, the points that should be paid attention to in the construction of white-light emitting materials as well as the potential adsorption mechanism for dyes and rare earth ions are deeply discussed.

Dammaranes from Gynostemma pentaphyllum and synthesis of their derivatives as inhibitors of protein tyrosine phosphatase 1B.

Protein tyrosine phosphatase 1B (PTP1B) is a key factor in the negative regulation of insulin pathway and a promising target for treatment of diabetes and obesity. Herein, the sapogenin 2b, prepared from the natural triterpene saponin 1b, was modified at 3-position to establish the dammarane derivatives library via esterification, oxidation and reductive amination reaction and evaluated as PTP1B inhibitors. 3-O-para-Carboxylphenyl substituted derivative 5b was found with the best in vitro inhibition activity to protein tyrosine phosphatase 1B (IC(50)=0.27microM), where 3-O-meta-carboxylphenyl substituted 5a exhibited the best selectivity (nearly fivefolds) between PTP1B and T-cell protein tyrosine phosphatase.

Tris(piperazinediium) phosphatododeca-molybo(V,VI)phosphate.

The title compound, (C(4)H(12)N(2))(3)[PMo(12)O(40)] or (H(2)pip)(3)[PMo(12)O(40)] (pip is piperazine), was prepared under hydro-thermal conditions. The asymmetric unit contains one-sixth of a mixed-valent Mo(V,VI) pseudo-Keggin-type [PMo(12)O(40)](6-) anion and half a piperazinediium cation, (H(2)pip)(2+). The discrete Keggin-type [PMo(12)O(40)](6- )anion has site symmetry and the three (H(2)pip)(2+) cations each have site symmetry at the centres of the mol-ecules. The central P atom is on special position , which is a roto-inversion position and generates the disorder of the PO(4) tetra-hedron. Furthermore, six doubly bridging oxide groups are also disordered with an occupancy factor of 0.5 for each O atom. The anions and cations are linked by an extensive network of inter-molecular N-H⋯O and C-H⋯O hydrogen bonds.

Poly[tetra-kis(2,2'-bipyridine)undeca-µ-oxido-hexa-oxidodicopper(II)hexa-vanadium(V)].

In the title organic-inorganic hybrid vanadate complex, [Cu(2)V(6)O(17)(C(10)H(8)N(2))(4)](n), the Cu(II) atom is six-coordinated by two chelating 2,2'-bipyridine (bipy) ligands and two vanadate O atoms in a distorted octa-hedral geometry. Two [Cu(bipy)(2)V(3)O(8)] units are linked by a bridging O atom, which lies on an inversion center, forming a dimeric unit. The dimeric units are further connected by bridging vanadate O atoms into a two-dimensional layer parallel to (100). The layers are connected by weak C-H⋯O hydrogen bonds.

Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.

Tau-tubulin kinase-1 (TTBK1) is involved in phosphorylation of tau protein at specific Serine/Threonine residues found in paired helical filaments, suggesting its role in tauopathy pathogenesis. We found that TTBK1 levels were upregulated in brains of human Alzheimer' disease (AD) patients compared with age-matched non-AD controls. To understand the effects of TTBK1 activation in vivo, we developed transgenic mice harboring human full-length TTBK1 genomic DNA (TTBK1-Tg). Transgenic TTBK1 is highly expressed in subiculum and cortical pyramidal layers, and induces phosphorylated neurofilament aggregation. TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin. Expression of recombinant TTBK1 in primary mouse cortical neurons significantly downregulated NR2B in a CDK5- and calpain-dependent manner. These data suggest that TTBK1 in AD brain may be one of the underlying mechanisms inducing CDK5 and calpain activation, NR2B downregulation, and subsequent memory dysfunction.