DREADD agonist 21 is an effective agonist for muscarinic-based DREADDs in vitro and in vivo

Chemogenetic tools such as designer receptors exclusively activated by designer drugs (DREADDs) are routinely used to modulate neuronal and non-neuronal signaling and activity in a relatively noninvasive manner. The first generation of DREADDs were templated from the human muscarinic acetylcholine receptor family and are relatively insensitive to the endogenous agonist acetylcholine but instead are activated by clozapine-N-oxide (CNO). Despite the undisputed success of CNO as an activator of muscarinic DREADDs, it has been known for some time that CNO is subject to a low rate of metabolic conversion to clozapine, raising the need for alternative chemical actuators of muscarinic-based DREADDs. Here we show that DREADD agonist 21 (C21) (11-(1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) is a potent and selective agonist at both excitatory (hM3Dq) and inhibitory (hM4Di) DREADDs and has excellent bioavailability, pharmacokinetic properties, and brain penetrability. We also show that C21-induced activation of hM3Dq and hM4Di in vivo can modulate bidirectional feeding in defined circuits in mice. These results indicate that C21 represents an alternative to CNO for in vivo studies where metabolic conversion of CNO to clozapine is a concern

Job satisfaction and its modeling among township health center employees: a quantitative study in poor rural China

<p>Abstract</p> <p>Background</p> <p>Job satisfaction is important to staff management of township health centers (THCs), as it is associated with organizational performance, quality of care and employee retention. The purpose of this study was to measure job satisfaction level of THC employees in poor rural China and to identify relevant features in order to provide policy advice on human resource development of health service institutions in poor regions.</p> <p>Methods</p> <p>A self-completion questionnaire was used to assess the job satisfaction and relevant features (response rate: 90.5%) among 172 employees (i.e., clinic doctors, medico-technical workers and public health workers) of 17 THCs in Anhui and Xinjiang provinces of China. The study covered a time period of two months in 2007.</p> <p>Results</p> <p>The mean staff job satisfaction scored 83.3, which was in the category of "somewhat satisfied" on a scale ranging from 0 (extremely dissatisfied) to 100 (extremely satisfied) by employing Likert's transformation formula. Exploratory factor analysis (EFA) revealed eight domains involved in modeling of job satisfaction, among which, the caregivers were more satisfied with job significance (88.2), job competency (87.9) and teamwork (87.7), as compared with work reward (72.9) and working conditions (79.7). Mean job satisfaction in Xinjiang (89.7) was higher than that in Anhui (75.5).</p> <p>Conclusions</p> <p>Employees of THCs have moderate job satisfactions in poor areas, which need to be raised further by improving their working conditions and reward.</p

An instrument to measure job satisfaction of nursing home administrators

BACKGROUND: The psychometric properties of the nursing home administrator job satisfaction questionnaire (NHA-JSQ) are presented, and the steps used to develop this instrument. METHODS: The NHA-JSQ subscales were developed from pilot survey activities with 93 administrators, content analysis, and a research panel. The resulting survey was sent to 1,000 nursing home administrators. Factor analyses were used to determine the psychometric properties of the instrument. RESULTS: Of the 1,000 surveys mailed, 721 usable surveys were returned (72 percent response rate). The factor analyses show that the items were representative of six underlying factors (i.e., coworkers, work demands, work content, work load, work skills, and rewards). CONCLUSION: The NHA-JSQ represents a short, psychometrically sound job satisfaction instrument for use in nursing homes

Reduced phosphorylation of brain insulin receptor substrate and Akt proteins in apolipoprotein-E4 targeted replacement mice

10.1038/srep03754Scientific Reports4

Mitochondrial DNA variants in inclusion body myositis

Mitochondrial DNA variants have been shown to be associated with many diseases. Mutations at mitochondrial DNA nucleotide positions 3192, 3196, 3397 and 4336 have been described in association with late-onset Alzheimer's disease. The pathological similarities between inclusion body myositis and Alzheimer's disease prompted an analysis of the relationship between the reported mutations and sporadic inclusion body myositis. The 4336G variant was not significantly increased in patients with inclusion body myositis or Alzheimer's disease when compared to controls. None of the patients with inclusion body myositis carried mutations at nucleotide positions 3192, 3196 and 3397. A transition at nucleotide position 4580 was detected in some patients with inclusion body myositis and Alzheimer's disease but was not significantly higher in frequency when compared to controls. Phylogenetic analysis showed that the 4336G and 4580A variants clustered together in their respective group. A group of patients with inclusion body myositis also clustered together on a separate branch of the phylogenetic tree. Closer investigation of this group revealed a common polymorphism at nucleotide position 16311. The frequency of the 16311C variant was higher in inclusion body myositis than in Alzheimer's disease and controls, although when only caucasian patients were considered the increased frequency was not statistically significant. Further studies will be required to determine whether this variant plays a role in the pathogenesis of inclusion body myositis