Discovery of [11C]MK-6884: a positron emission tomography (PET) imaging agent for the study of M4 muscarinic receptor positive allosteric modulators (PAMs) in neurodegenerative diseases

The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development of CNS directed therapeutics. We and others have investigated muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs) for the treatment of symptoms associated with neuropsychiatric disorders. In this article, we describe the synthesis, in vitro, and in vivo characterization of a series of central pyridine-related M4 PAMs that can be conveniently radiolabeled with carbon-11 as PET tracers for the in vivo imaging of an allosteric binding site of the M4 receptor. We first demonstrated its feasibility by mapping the receptor distribution in mouse brain and confirming that a lead molecule 1 binds selectively to the receptor only in the presence of the orthosteric agonist carbachol. Through a competitive binding affinity assay and a number of physiochemical properties filters, several related compounds were identified as candidates for in vivo evaluation. These candidates were then radiolabeled with 11C and studied in vivo in rhesus monkeys. This research eventually led to the discovery of the clinical radiotracer candidate [11C]MK-6884

Cure of Filament-Caused MBR Fouling in the Presence of Antibiotics: Taking Ciprofloxacin Exposure As an Example

Pharmaceuticals and personal care products (PPCPs) are ubiquitous in wastewater streams, but little is known regarding their roles in membrane fouling during the operation of membrane bioreactors (MBRs). This study attempted to understand the role of ciprofloxacin exposure in control of filamentous bulking as well as membrane fouling mitigation. Compared with the control MBR, results show that the ciprofloxacin could selectively inhibit and kill filaments present in the mixed liquor, and, as a consequence, the sludge settleability improved significantly. The addition of ciprofloxacin had little influence on organic removals and nitrification, but had an adverse effect on denitrification. In addition, the sludge flocs exposure to ciprofloxacin still kept in compact structure; specifically, granular sludge was finally formed possibly due to the increase of polysaccharides in extracellular polymeric substances (EPS). Characterization by nuclear magnetic resonance (NMR) corroborated the enrichment of polysaccharides in the EPS exposure to ciprofloxacin. On the other hand, because of the release of EPS and the decay of filaments, soluble microbial products (SMP), particularly soluble polysaccharides, increased significantly in the MBR exposure to ciprofloxacin. Despite this, the results of this study show that the presence of trace contaminants in wastewater streams may play some positive roles in MBR fouling control

Preparation and adsorption properties of magnetic chitosan/sludge biochar composites for removal of Cu2+ ions

Abstract The magnetic chitosan/sludge biochar composite adsorbent was prepared using chitosan, Fe3O4, and sludge biochar as raw materials. The composite adsorbent was able to achieve rapid solid–liquid separation under an applied magnetic field. The morphology and microstructure of the composite adsorbent were characterized by FTIR, XRD, SEM, VSM, and BET analysis. The adsorption performance of the composite adsorbent on Cu2+ was investigated through static adsorption experiments, and the effects of adsorbent dosage, initial concentration of Cu2+, initial pH of the solution, and adsorption temperature on the adsorption efficiency of Cu2+ were discussed. The results showed that chitosan and Fe3O4 were successfully loaded on sludge biochar. When the initial concentration of Cu2+ was 30 mg/L, the dosage of the magnetic chitosan/sludge biochar composite material was 0.05 g, the adsorption time was 180 min, pH was 5, and the temperature was room temperature, the maximum removal rate of Cu2+ reached 99.77%, and the maximum adsorption capacity was 55.16 mg/g. The adsorption kinetics and adsorption isotherm data fitted well with the pseudo-second-order kinetic model and Langmuir adsorption isotherm model, indicating that the adsorption process was chemisorption with monolayer coverage

Cure of Filament-Caused MBR Fouling in the Presence of Antibiotics: Taking Ciprofloxacin Exposure As an Example

Pharmaceuticals and personal care products (PPCPs) are ubiquitous in wastewater streams, but little is known regarding their roles in membrane fouling during the operation of membrane bioreactors (MBRs). This study attempted to understand the role of ciprofloxacin exposure in control of filamentous bulking as well as membrane fouling mitigation. Compared with the control MBR, results show that the ciprofloxacin could selectively inhibit and kill filaments present in the mixed liquor, and, as a consequence, the sludge settleability improved significantly. The addition of ciprofloxacin had little influence on organic removals and nitrification, but had an adverse effect on denitrification. In addition, the sludge flocs exposure to ciprofloxacin still kept in compact structure; specifically, granular sludge was finally formed possibly due to the increase of polysaccharides in extracellular polymeric substances (EPS). Characterization by nuclear magnetic resonance (NMR) corroborated the enrichment of polysaccharides in the EPS exposure to ciprofloxacin. On the other hand, because of the release of EPS and the decay of filaments, soluble microbial products (SMP), particularly soluble polysaccharides, increased significantly in the MBR exposure to ciprofloxacin. Despite this, the results of this study show that the presence of trace contaminants in wastewater streams may play some positive roles in MBR fouling control

An Initial Damage Model of Rock Materials under Uniaxial Compression Considering Loading Rates

Existing rock material damage models always ignore the initial damage characteristics of rock materials, and the actual rock materials have initial damage characteristics. To consider the rock’s initial damage characteristics, a series of compression tests for yellow sandstone was carried out. First, the acoustic emission characteristics and damage model of yellow sandstone, considering the loading rates, were analyzed. Second, an initial damage model, which can better describe the initial damage characteristics of yellow sandstone materials, is presented. The research results show that the strength and elastic modulus of yellow sandstone depends on the loading rate, and increases as the loading rate increases

Numerical Analysis of Ground Settlement Patterns Resulting from Tunnel Excavation in Composite Strata

Cross-river twin tunnels are prone to deformation and uneven settlement of the surrounding soil due to the complexity of the strata crossed, which has a negative impact on the tunnel structure. A numerical calculation model was established using the COMSOL Multiphysics to study the effects of twin tunnel excavation in composite strata on the ground settlement and the ground settlement pattern. The results indicated that after the construction of the twin tunnels is completed, the ground settlement above the first tunnel is slightly larger than the ground settlement above the second tunnel. The further the spacing between the two tunnels before and after excavation, the smaller the amount of ground settlement and the impact on the surrounding soil. The ground settlement value increases with the increase in burial depth, and the ground settlement curve gradually changes from a W-shaped curve to a V-shaped curve. As the distance between the two tunnels increases, the maximum settlement value of the settlement curve gradually decreases, and the ground lateral settlement curve changes from V-shaped to W-shaped. The higher the water level on the riverbed side, the greater the settlement value of the ground

Antimicrobial peptide nanoparticles coated with macrophage cell membrane for targeted antimicrobial therapy of sepsis

Sepsis is a serious life-threatening disease. Bacterial infection is one of the main causes of sepsis. Although etiopathogenesis is gradually understood, the treatment is still scarce. Mortality caused by sepsis is still challenge. Herein, macrophage membrane coated antimicrobial peptide nanoparticles (M−AMPNP) was explored based on the specific binding of bacterial recognition receptors on macrophage membrane to bacteria. M−AMPNP was used to treat sepsis caused by bacterial infection. In vivo results showed that M−AMPNP was effectively delivered and retained at the site of infection by intravenous injection, which reduced the level of inflammatory factors and ultimately gave infected mice a significant survival advantage. M−AMPNP provides a potential strategy for targeted therapy of sepsis

Characterization of Mu-Like Yersinia Phages Exhibiting Temperature Dependent Infection

ABSTRACT Yersinia pestis is the etiological agent of plague. Marmota himalayana of the Qinghai-Tibetan plateau is the primary host of flea-borne Y. pestis. This study is the report of isolation of Mu-like bacteriophages of Y. pestis from M. himalayana. The isolation and characterization of four Mu-like phages of Y. pestis were reported, which were named as vB_YpM_3, vB_YpM_5, vB_YpM_6, and vB_YpM_23 according to their morphology. Comparative genome analysis revealed that vB_YpM_3, vB_YpM_5, vB_YpM_6, and vB_YpM_23 are phylogenetically closest to Escherichia coli phages Mu, D108 and Shigella flexneri phage SfMu. The role of LPS core structure of Y. pestis in the phages’ receptor was pinpointed. All the phages exhibit “temperature dependent infection,” which is independent of the growth temperature of the host bacteria and dependent of the temperature of phage infection. The phages lyse the host bacteria at 37°C, but enter the lysogenic cycle and become prophages in the chromosome of the host bacteria at 26°C. IMPORTANCE Mu-like bacteriophages of Y. pestis were isolated from M. himalayana of the Qinghai-Tibetan plateau in China. These bacteriophages have a unique temperature dependent life cycle, follow a lytic cycle at the temperature of warm-blooded mammals (37°С), and enter the lysogenic cycle at the temperature of its flea-vector (26°С). A switch from the lysogenic to the lytic cycle occurred when lysogenic bacteria were incubated from lower temperature to higher temperature (initially incubating at 26°C and shifting to 37°C). It is speculated that the temperature dependent lifestyle of bacteriophages may affect the population dynamics and pathogenicity of Y. pestis

Hyaluronic acid facilitates bone repair effects of calcium phosphate cement by accelerating osteogenic expression

Calcium phosphate cements (CPC) are widely anticipated to be an optimum bone repair substitute due to its satisfied biocompatibility and degradability, suitable to be used in minimally invasive treatment of bone defects. However the clinical application of CPC is still not satisfied by its poor cohesiveness and mechanical properties, in particular its osteoinductivity. Hyaluronic acid reinforced calcium phosphate cements (HA/CPC) showed extroadinary potential not only enhancing the compressive strength of the cements but also significantly increasing its osteoinductivity. In our study, the compressive strength of HA/CPC increased significantly when the cement was added 1% hyaluronic acid (denoted as 1-HA/CPC). In the meantime, hyaluronic acid obviously promoted ALP activity, osteogenic related protein and mRNA expression of hBMSCs (human bone marrow mesenchymal stem cells) in vitro, cement group of HA/CPC with 4% hyaluronic acid adding (denoted as 4-HA/CPC) showed optimal enhancement in hBMSCs differentiation. After being implanted in rat tibial defects, 4-HA/CPC group exhibited better bone repair ability and bone growth promoting factors, comparing to pure CPC and 1-HA/CPC groups. The underlying biological mechanism of this stimulation for HA/CPC may be on account of higher osteogenic promoting factors secretion and osteogenic genes expression with hyaluronic acid incorporation. These results indicate that hyaluronic acid is a highly anticipated additive to improve physicochemical properties and osteoinductivity performance of CPCs for minimally invasive healing of bone defects