Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target–inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the P. falciparum resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.

To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.

No abstract

No abstract

No abstract

Recent studies at the cellular and regional levels have pointed out the multifaceted importance of neural synchronization and temporal variance of neural activity. For example, neural synchronization and temporal variance has been shown by us to be altered in patients in the vegetative state (VS). This finding nonetheless leaves open the question of whether these abnormalities are specific to VS or rather more generally related to the absence of consciousness. The aim of our study was to investigate the changes of inter- and intra-regional neural synchronization and temporal variance of resting state activity in anesthetic-induced unconsciousness state. Applying an intra-subject design, we compared resting state activity in functional magnetic resonance imaging (fMRI) between awake versus anesthetized states in the same subjects. Replicating previous studies, we observed reduced functional connectivity within the default mode network (DMN) and thalamocortical network in the anesthetized state. Importantly, intra-regional synchronization as measured by regional homogeneity (ReHo) and temporal variance as measured by standard deviation (SD) of the BOLD signal were significantly reduced in especially the cortical midline regions, while increased in the lateral cortical areas in the anesthetized state. We further found significant frequency-dependent effects of SD in the thalamus, which showed abnormally high SD in Slow-5 (0.01-0.027 Hz) in the anesthetized state. Our results show for the first time of altered temporal variance of resting state activity in anesthesia. Combined with our findings in the vegetative state, these findings suggest a close relationship between temporal variance, neural synchronization and consciousness.

No abstract

Musculoskeletal diseases often have concomitant psychological disorders, such as depression and anxiety. Frozen shoulder (FS) is a musculoskeletal disease, and causes pain and stiffness in the shoulder. The relationship between FS and psychological disorders has rarely been investigated. This cross-sectional study was to evaluate the risk of depression and anxiety in patients with primary FS, and to explore the relationship between psychological disorders and disease status. In this study, anxiety and depression were evaluated in 124 patients (78 women and 46 men) with primary FS, compared with 130 (72 women and 58 men) age-, sex- and education matched healthy controls between March 2009 and June 2012. Simple shoulder test (SST); shoulder pain and disability index (SPADI); the range of motion (ROM); visual analog scales (VAS) for pain and sleep disturbances; hospital anxiety and depression scale for depression (HADS-D) and for anxiety (HADS-A); and health assessment questionnaire (HAQ) were used to assess clinical and psychological status. In FS patients, the prevalence of depression and anxiety was 28.2 and 24.2%, respectively. Compared with the healthy controls, higher HADS-D (6.41 ± 3.69, 5. 23 ± 2.87 p = 0.006) and HADS-A (6.16 ± 3.62, 4.90 ± 3.05 p = 0.003) were detected. The FS patients with depression or anxiety had significantly lower SST and HAQ scores, significantly higher VAS and SPADI scores and significantly higher prevalence of sleep disturbances compared with the FS patients with normal psychological status. The correlations of SST, SPADI, VAS and sleep disturbances but not ROM with HADS-A and HADS-D were significant ( p < 0.05). This finding indicates that anxiety and depression may coexist with FS; patients with psychological disorders have more severe self-reported shoulder pain and functional restriction.