Structure-activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4

There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M4) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M4 positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a suitable M4 PET ligand that allows the non-invasive visualization of M4 in the brain. Structure-activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound 12 - a subtype-selective positive allosteric modulator (PAM). The radiofluorinated analogue, [18F] 12, was synthesized in 28 ± 10% radiochemical yield, >37 GBq/μmol and an excellent radiochemical purity >99%. Initial in vitro autoradiograms on rodent brain sections were performed in the absence of carbachol and showed moderate specificity as well as a low selectivity of [18F] 12 for the M4-rich striatum. However, in the presence of carbachol, a significant increase in tracer binding was observed in the rat striatum, which was reduced by >60% under blocking conditions, thus indicating that orthosteric ligand interaction is required for efficient binding of [18F] 12 to the allosteric site. Remarkably, however, the presence of carbachol was not required for high specific binding in the non-human primate (NHP) and human striatum, and did not further improve the specificity and selectivity of [18F] 12 in higher species. These results pointed towards significant species-differences and paved the way for a preliminary PET study in NHP, where peak brain uptake of [18F] 12 was found in the putamen and temporal cortex. In conclusion, we report on the identification and preclinical development of the first radiofluorinated M4 PET radioligand with promising attributes. The availability of a clinically validated M4 PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.

18FMAGL-4-11 positron emission tomography molecular imaging of monoacylglycerol lipase changes in preclinical liver fibrosis models

Monoacylglycerol lipase (MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol (2-AG) into the proinflammatory eicosanoid precursor arachidonic acid (AA). MAGL and other endogenous cannabinoid (EC) degrading enzymes are involved in the fibrogenic signaling pathways that induce hepatic stellate cell (HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an 18F-labeled MAGL inhibitor ([18F]MAGL-4-11) for PET imaging and demonstrated highly specific binding in vitro and in vivo. In this study, we determined [18F]MAGL-4-11 PET enabled imaging MAGL levels in the bile duct ligation (BDL) and carbon tetrachloride (CCl4) models of liver cirrhosis; we also assessed the hepatic gene expression of the enzymes involved with EC system including MAGL, NAPE-PLD, FAAH and DAGL that as a function of disease severity in these models; [18F]MAGL-4-11 autoradiography was performed to assess tracer binding in frozen liver sections both in animal and human. [18F]MAGL-4-11 demonstrated reduced PET signals in early stages of fibrosis and further significantly decreased with disease progression compared with control mice. We confirmed MAGL and FAAH expression decreases with fibrosis severity, while its levels in normal liver tissue are high; in contrast, the EC synthetic enzymes NAPE-PLD and DAGL are enhanced in these different fibrosis models. In vitro autoradiography further supported that [18F]MAGL-4-11 bound specifically to MAGL in both animal and human fibrotic liver tissues. Our PET ligand [18F]MAGL-4-11 shows excellent sensitivity and specificity for MAGL visualization in vivo and accurately reflects the histological stages of liver fibrosis in preclinical models and human liver tissues.

Recent developments on PET radiotracers for TSPO and their applications in neuroimaging

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.

Development of a highly-specific

As a serine hydrolase, monoacylglycerol lipase (MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS), leading to the formation of arachidonic acid (AA). Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms, including neuroinflammation, cognitive impairment, epileptogenesis, nociception and neurodegenerative diseases. Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions, and a MAGL positron emission tomography (PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors. Herein, we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates. Pharmacological evaluation of these candidates by activity-based protein profiling identified

Circulation and etiological characterization of Salmonella enterica serotype in human in Guangdong province, 2007-2016 / 中华流行病学杂志

Objective: To understand the circulation, drug resistance and molecular characteristics of Salmonella1, 4, [5], 12: i:- in human in Guangdong province. Methods:Salmonella1, 4, [5], 12: i:- isolated from diarrhea patients in Guangdong during 2007-2016 were detected for drug resistance, genes and PFGE characteristics. Results: A total of 2 960 strains Salmonella1, 4, [5], 12: i: - were isolated from human diarrhea cases during this period. The positive rates of the isolation increased year by year. The male to female ratio of the infection cases was 1.58∶1, and the infection mainly occurred in infants and young children. Except imipenem, Salmonella1, 4, [5], 12: i: - was resistant to other 17 antibiotics to some extent. The drug resistant rates to ceftazidime, cefotaxime and ciprofloxacin increased from 2011 to 2016. Multi-drug resistance was serious, for example, the multi-drug resistant strains with ASSuT accounted for 70.62% (435/616) and the multi-drug resistant strains with ACSuGSTTm accounted for 27.11% (167/616). The lack of fljA, fljB and hin genes, as well as the retaining of iroB, STM2740, STM2757 genes, resulted in the unable expression of FljBenx gene with 8 different defection profiles. There were 934 different PFGE patterns observed in 2 347 strains, which displayed a relatively large fingerprint polymorphism. The major PFGE pattern was JPXX01. GD0226, which was found in 97 strains, accounting for 4.13% (97/2 347). The PFGE patterns in 168 Salmonella1, 4, [5], 12: i: - strains were consistent with that of Salmonella typhimurium. Conclusions:Salmonella1,4,[5], 12: i: - strains has become the major serotype of Salmonella that cause diarrhea in human in Guangdong. The multi-drug resistance of Salmonella1,4, [5], 12: i: - was serious, and since the defection of fljA, fljB and hin genes, the expression of FljBenx protein failed. The PFGE results were diverse, which displayed polymorphism in inheritance.

Study on prevalence of physical activity in rural residents in four counties (districts) of Shanxi and Chongqing / 中华流行病学杂志

Objective: To investigate the prevalence of physical activity and its influencing factors in rural residents in Shanxi and Chongqing. Methods: In four counties (districts) of Shanxi and Chongqing, local residents aged ≥18 who lived there for more than one year and had no plan to migrate to other areas in 2 years were surveyed through face to face questionnaire interviews to collect the information about their daily physical activity time, sedentary time, related knowledge and attitude, and others. Results: The physical inactivity rate of the residents was 14.9%, and 88.7% of residents never took daily physical activity. The average sedentary time was (3.91±2.06) hours. The results of multivariate analysis showed that education level, per capita monthly income and activity degree were the factors influencing physical inactivity. Conclusion: The proportion of people who never took daily physical activity in the survey area was higher than the average level in rural areas in China, so measures should be taken to improve the overall rate of physical activity. For people who have exercise willingness, but have no practice, and those who have already increased their physical activities, targeted guidance is needed on the basis of strengthened health education.

A prospective cohort study on the relationship between maternal prenatal depressive symptoms and children's behavioral problems at 2 years old / 中华流行病学杂志

Objective: To explore the associations between maternal and prenatal depressive symptoms and children's behavioral problems at 2 years old. Methods: In the present study, a total of 491 mother-child pairs were selected from the Shanghai-Minhang Birth Cohort Study (S-MBCS) which was conducted in Maternal and Child Health Hospital of Minhang District in Shanghai between April and December, 2012. Data from the Center for Epidemiologic Studies on Depression was gathered to assess the maternal depressive symptoms in the second and third trimester of pregnancy, as well as at 6 months and 12 months postpartum. Neurodevelopment at 2 years was assessed, using the Child Behavior Checklist. We used generalized linear models with a log-link function and a Binomial distribution to estimate the risk ratios (RRs) and 95%CIs, on children's behavioral problems at 2 years of age. Sensitivity analyses were performed among participants without postpartum depressive symptoms. Results: After adjustment on factors as maternal age, gestation week, average monthly income per person, parental education and children's gender etc., maternal depression in second trimester of pregnancy was found associated with higher risk of both developing emotional (RR=2.61, 95%CI: 1.36-4.99) and internalizing problems (RR=1.94, 95%CI: 1.22-3.08). However, maternal depression in third trimester was found to be associated with higher risks of developing emotional (RR=6.46, 95%CI: 3.09-13.53), withdrawn (RR=2.42, 95%CI: 1.16-5.02), aggressive (RR=2.93, 95%CI: 1.45-5.94), internalizing (RR=1.79, 95%CI: 1.01-3.16) or externalizing problems (RR=2.56, 95%CI:1.49-4.42). In sensitivity analysis, antenatal maternal depression was found positively associated with children's emotional, internalizing and externalizing problems and the differences all statistically significant. Conclusions: Maternal depression during pregnancy might increase the risks of children's behavioral problems. In order to decrease the incidence of children's behavioral problems and promoting both maternal and child health status, monitoring program regarding maternal mental health care should be strengthened.

Gaseous phase benzene decomposition by non-thermal plasma coupled with nano titania catalyst

Synergistic effect of atmospheric non-thermal plasma generated by dielectric barrier discharge and nano titania photocatalyst for benzene decomposition was tested. The paper indicated the effect of photocatalyst on removal efficiency of benzene, the compare of photocatalyst characteristic in different high temperatures by heat treatment, analysis of by-products. The results showed that the effect of degradation was visible by added photocatalyst in the plasma reactor. When concentration of benzene was 600 mg/m[3] and electric field strength was 10 kV/cm, the removal efficiency of benzene was increased up to 81% without photocatalyst. At the same condition, the removal efficiency was increased to 15% higher with photocatalyst. Nano titania crystal was anatase crystal in 450 °C heat treatment which is best for benzene removal. The plasma reactor packed with photocatalyst shows a better selectivity of carbon dioxide than that without photocatalyst. By-products are mostly carbon dioxide, water and a small quantity of carbon monoxide

Spatial and temporal distribution in density and biomass of two Pseudodiaptomus species (Copepoda: Calanoida) in the Caeté river estuary (Amazon region - North of Brazil)

Spatial and temporal density and biomass distribution of the planktonic copepods Pseudodiaptomus richardi and P. acutus along a salinity gradient were investigated in the Caeté River Estuary (North-Brazil) in June and December, 1998 (dry season) and in February and May, 1999 (rainy season). Copepod biomass was estimated using regression parameters based on the relation of dry weight and body length (prosome) of adult organisms. The Caeté River Estuary was characterized by high spatial and temporal variations in salinity (0.8-37.2‰). Exponential length-weight relationships were observed for both Pseudodiaptomus species. Density and biomass values oscillated between 0.28-46.18 ind. m-3 and 0.0022-0.3507 mg DW. m-3 for P. richardi; and between 0.01-17.02 ind. m-3 and 0.0005-0.7181 mg DW. m-3 for P. acutus. The results showed that the contribution of P. richardi for the secondary production in the Caeté River Estuary is more important in the limnetic zone than in other zones where euhaline-polyhaline regimes were predominant. However, it was not possible to observe a clear pattern of spatial and temporal distribution for P. acutus.

A distribuição espacial e temporal da densidade e biomassa dos copépodos planctônicos Pseudodiaptomus richardi e P. acutus, ao longo de um gradiente de salinidade, foi estudada no Estuário do Rio Caeté (Norte do Brasil) durante os meses de junho e dezembro de 1998 (estação seca) e fevereiro e maio de 1999 (estação chuvosa). A biomassa dos copépodos foi estimada a partir de parâmetros da regressão baseada na relação entre o peso seco e o comprimento do corpo (prossoma) de organismos adultos. O Estuário do Rio Caeté caracterizou-se por uma grande variação espacial e sazonal na salinidade (0,8-37,2‰). A relação peso-comprimento para ambas as espécies de Pseudodiaptomus foi do tipo exponencial. Os valores de densidade e biomassa oscilaram entre 0,28-46,18 ind. m-3 e 0,0022-0,3507 mg DW. m-3 para P. richardi; e entre 0,01-17,02 ind. m-3 e 0,0005-0,7181 mg DW. m-3 para P. acutus. Os resultados revelaram que a contribuição de P. richardi para a produção secundária no Estuário do Rio Caeté é mais importante na zona liminética que em outras zonas onde foram dominantes os regimes eurihalino-polihalino. Contudo, para P. acutus não foi possível observar de forma clara um padrão de distribuição espacial e temporal para a área estudada.