G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans.

G protein-coupled receptors (GPCRs) regulate many animal behaviors. GPCR signaling is mediated by agonist-promoted interactions of GPCRs with heterotrimeric G proteins, GPCR kinases (GRKs), and arrestins. To further elucidate the role of GRKs in regulating GPCR-mediated behaviors, we utilized the genetic model system Caenorhabditis elegans Our studies demonstrate that grk-2 loss-of-function strains are egg laying-defective and contain low levels of serotonin (5-HT) and high levels of the 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA). The egg laying defect could be rescued by the expression of wild type but not by catalytically inactive grk-2 or by the selective expression of grk-2 in hermaphrodite-specific neurons. The addition of 5-HT or inhibition of 5-HT metabolism also rescued the egg laying defect. Furthermore, we demonstrate that AMX-2 is the primary monoamine oxidase that metabolizes 5-HT in C. elegans, and we also found that grk-2 loss-of-function strains have abnormally high levels of AMX-2 compared with wild-type nematodes. Interestingly, GRK-2 was also found to interact with and promote the phosphorylation of AMX-2. Additional studies reveal that 5-HIAA functions to inhibit egg laying in a manner dependent on the 5-HT receptor SER-1 and the G protein GOA-1. These results demonstrate that GRK-2 modulates 5-HT metabolism by regulating AMX-2 function and that 5-HIAA may function in the SER-1 signaling pathway

mTreeIllustrator: A Mixed-Initiative Framework for Visual Exploratory Analysis of Multidimensional Hierarchical Data

Multidimensional hierarchical (mTree) data are very common in daily life and scientific research. However, mTree data exploration is a laborious and time-consuming process due to its structural complexity and large dimension combination space. To address this problem, we present mTreeIllustrator, a mixed-initiative framework for exploratory analysis of multidimensional hierarchical data with faceted visualizations. First, we propose a recommendation pipeline for the automatic selection and visual representation of important subspaces of mTree data. Furthermore, we design a visual framework and an interaction schema to couple automatic recommendations with human specifications to facilitate progressive exploratory analysis. Comparative experiments and user studies demonstrate the usability and effectiveness of our framework

The experience of long-stay patients in a forensic psychiatric hospital in China: a qualitative study

open access articleBackground Long stay in forensic psychiatric hospitals is common in patients who are defined as “not criminally responsible on account of mental disorder”. However, little is known about how these patients experience and perceive the long stay within these settings. The aim of this study is to explore the perception and needs of long-stay patients in forensic psychiatric hospitals in China. Methods In-depth semi-structured interviews were conducted with 21 participants who had lived in the forensic psychiatry hospital for more than 8 years. We used thematic analysis strategies to analyse the qualitative data. Results Participants’ perceptions clustered seven themes: hopelessness, loneliness, worthlessness, low mood, sleep disturbances, lack of freedom, and lack of mental health intervention. Conclusions The views and opinions expressed by long-stay patients showed that psychological distress is prevailing in forensic psychiatric hospitals. Adequate and effective care and mental health interventions are recommended to be tailored for their special needs

Adaptive mesh refinement for finite element analysis of the free vibration disturbance of cylindrical shells due to circumferential micro-crack damage

Purpose Moderately thick circular cylindrical shells are widely used as supporting structures or storage cavities in structural engineering, rock engineering, and aerospace engineering. In practical engineering, shells often work with micro-cracks or defects. The existence of micro-crack damage may result in the disturbance of dynamic behaviours and even induce accidental dynamic disasters. The free vibration frequency and mode are important parameters for the dynamic performance and damage identification analysis. In particular, stiffness weakening of the local damage region leads to significant changes in the vibration mode, which makes it difficult for the mesh generated in the conventional finite element method to capture a high-precision solution of the local oscillation. Design/methodology/approach In response to the above problems, this study developed an adaptive finite element method and a crack damage characterisation method for moderately thick circular cylindrical shells. By introducing the inverse power iteration method, error estimation, and mesh subdivision refinement technique for the analysis of finite element eigenvalue problems, an adaptive computation scheme was constructed for the free vibration problem of moderately thick circular cylindrical shells with circumferential crack damage. Findings Based on typical numerical examples, the established adaptive finite element solution for the free vibration of moderately thick circular cylindrical shells demonstrated its suitability for solving the high-precision free vibration frequency and mode of cylindrical shell structures. The any order frequency and mode shape of cracked cylindrical shells under the conditions of different ring wave numbers, crack locations, crack depths, and multiple cracks were successfully solved. The influences of the location, depth, and number of cracks on the disturbance of dynamic behaviours were analysed. Originality/value This study can be used as a reference for the adaptive finite element solution of free vibration of moderately thick circular cylindrical shells with cracks and lays the foundation for further development of a high-performance computation method suitable for the dynamic disturbance and damage identification analysis of general cracked structures

A Recalibrated Molecular Clock and Independent Origins for the Cholera Pandemic Clones

Cholera, caused by Vibrio cholerae, erupted globally from South Asia in 7 pandemics, but there were also local outbreaks between the 6th (1899–1923) and 7th (1961–present) pandemics. All the above are serotype O1, whereas environmental or invertebrate isolates are antigenically diverse. The pre 7th pandemic isolates mentioned above, and other minor pathogenic clones, are related to the 7th pandemic clone, while the 6th pandemic clone is in the same lineage but more distantly related, and non-pathogenic isolates show no clonal structure. To understand the origins and relationships of the pandemic clones, we sequenced the genomes of a 1937 prepandemic strain and a 6th pandemic isolate, and compared them with the published 7th pandemic genome. We distinguished mutational and recombinational events, and allocated these and other events, to specific branches in the evolutionary tree. There were more mutational than recombinational events, but more genes, and 44 times more base pairs, changed by recombination. We used the mutational single-nucleotide polymorphisms and known isolation dates of the prepandemic and 7th pandemic isolates to estimate the mutation rate, and found it to be 100 fold higher than usually assumed. We then used this to estimate the divergence date of the 6th and 7th pandemic clones to be about 1880. While there is a large margin of error, this is far more realistic than the 10,000–50,000 years ago estimated using the usual assumptions. We conclude that the 2 pandemic clones gained pandemic potential independently, and overall there were 29 insertions or deletions of one or more genes. There were also substantial changes in the major integron, attributed to gain of individual cassettes including copying from within, or loss of blocks of cassettes. The approaches used open up new avenues for analysing the origin and history of other important pathogens

Photon-noise limited sensitivity in titanium nitride kinetic inductance detectors

We demonstrate photon-noise limited performance at sub-millimeter wavelengths in feedhorn-coupled, microwave kinetic inductance detectors (MKIDs) made of a TiN/Ti/TiN trilayer superconducting film, tuned to have a transition temperature of 1.4~K. Micro-machining of the silicon-on-insulator wafer backside creates a quarter-wavelength backshort optimized for efficient coupling at 250~\micron. Using frequency read out and when viewing a variable temperature blackbody source, we measure device noise consistent with photon noise when the incident optical power is $>$~0.5~pW, corresponding to noise equivalent powers $>$~3$\times 10^{-17}$ W/$\sqrt{\mathrm{Hz}}$. This sensitivity makes these devices suitable for broadband photometric applications at these wavelengths

7-Pyrrolidinethoxy-4′-Methoxyisoflavone Prevents Amyloid β–Induced Injury by Regulating Histamine H3 Receptor-Mediated cAMP/CREB and AKT/GSK3β Pathways

In studies on the treatment of Alzheimer’s disease (AD), in which cognition is enhanced even modestly or selectively, it has been considered that the histamine H3 receptor (H3R) may be a potential target. In this study, we aimed at evaluating the ability of 7-pyrrolidinethoxy-4′-methoxyisoflavone (indicated as LC1405), a novel potential H3R antagonist identified from our H3R antagonist screening system, to ameliorate amyloid β (Aβ)-induced cognitive deficits, and to explore the underlying mechanisms that are related to H3R-modulated signaling. Our results demonstrated that LC1405 effectively reduced the progression of Aβ-associated disorders, such as improved learning and memory capabilities, preserved tissues from suffering neurodegeneration and ultrastructural abnormalities, and ameliorated cholinergic dysfunction in an APP/PS1 double transgenic mouse model of AD. In an in vitro model, LC1405 protected neuronal cells against copper-induced Aβ toxicity, as demonstrated by the improvement in cell viability and decrease in neuronal apoptotic ratio. In addition, treatment with LC1405 resulted in the up-regulation of acetylcholine (ACh) or histamine release and provided neuroprotection through cellular signaling cascades involving H3R-mediated cAMP/CREB and AKT/GSK3β pathways. Furthermore, the beneficial effects of LC1405 on Aβ-mediated toxicity and H3R-mediated cAMP/CREB and AKT/GSK3β axes were reversed after pharmacological activation of H3R. In conclusion, our results demonstrated that LC1405 blocked Aβ-induced toxicity through H3R-modulated signaling transduction both in vitro and in vivo. The results also suggested that LC1405 might have translational potential as a complementary therapy to control disease progression in AD patients who developed cognitive deficits with H3R-related ACh neurotransmission abnormality