Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik−/−/Apcmin/+ mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apcmin/+ mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach.

Electroencephalogram (EEG) phase synchronization analyses can reveal large-scale communication between distant brain areas. However, it is not possible to identify the directional information flow between distant areas using conventional phase synchronization analyses. In the present study, we applied transcranial magnetic stimulation (TMS) to the occipital area in subjects who were resting with their eyes closed, and analyzed the spatial propagation of transient TMS-induced phase resetting by using the transfer entropy (TE), to quantify the causal and directional flow of information. The time-frequency EEG analysis indicated that the theta (5 Hz) phase locking factor (PLF) reached its highest value at the distant area (the motor area in this study), with a time lag that followed the peak of the transient PLF enhancements of the TMS-targeted area at the TMS onset. Phase-preservation index (PPI) analyses demonstrated significant phase resetting at the TMS-targeted area and distant area. Moreover, the TE from the TMS-targeted area to the distant area increased clearly during the delay that followed TMS onset. Interestingly, the time lags were almost coincident between the PLF and TE results (152 vs. 165 ms), which provides strong evidence that the emergence of the delayed PLF reflects the causal information flow. Such tendencies were observed only in the higher-intensity TMS condition, and not in the lower-intensity or sham TMS conditions. Thus, TMS may manipulate large-scale causal relationships between brain areas in an intensity-dependent manner. We demonstrated that single-pulse TMS modulated global phase dynamics and directional information flow among synchronized brain networks. Therefore, our results suggest that single-pulse TMS can manipulate both incoming and outgoing information in the TMS-targeted area associated with functional changes.

We identified eight patients with bronchiolitis obliterans (BO) in the autopsies of 81 bone marrow transplant (BMT) recipients. Rapidly progressive dyspnoea and cough were the main presenting symptoms in all eight patients, associated with overinflation and/or infiltrative opacity seen on chest X-ray and obstructive disorder revealed by pulmonary function tests. Early lesions were characterized by epithelial loss and an inflammatory infiltrate containing foamy histiocytes with mild luminal narrowing. Partial or total occlusion of the bronchiolar lumina by fibrous connective tissue was the feature of late lesions. Both changes were coexistent in all cases. In one case, small bronchi with cartilage were also affected by the obstructive process, showing bronchitis obliterans. All eight patients showed non-obstructive broncho-bronchiolitis characterized by denuding of respiratory epithelium, mural oedema and an inflammatory infiltrate in addition to BO, and these changes were also seen in 18 patients without BO. The submucosal glands of large bronchi and the trachea showed mucous retention and a mild inflammatory infiltrate in four of the eight patients. Coexistent infectious processes were seen in all cases, cytomegalovirus and Aspergillus being the most frequent organisms. BO probably develops as an immunopathological event related to graft-versus-host disease (GVHD) during the impaired immune status phase of the post-BMT period, possibly initiated by infection. Bronchial gland involvement in chronic GVHD is one of the factors responsible for this abnormal immune status.

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To identify protein(s) with different expression patterns in the mushroom bodies (MBs) in the honeybee brain, we compared the protein profiles of MBs and optic lobes (OLs) using proteomics. Two-dimensional gel electrophoresis revealed that five and three spots were selectively expressed in the MBs or OLs, respectively. Liquid chromatography tandem mass spectrometry analysis identified juvenile hormone diol kinase and glyceraldehyde-3-phosphate dehydrogenase as MB-and OLselective proteins, respectively. In situ hybridization revealed that jhdk expression was upregulated in MB neuron subsets, whereas gapdh expression was downregulated, indicating that MBs have a distinct gene and protein expression profile in the honeybee brain.

The PSIs correlated with performance on the activities of daily living scale but not with scores on a pure motor impairment scale. These results suggest that large-scale phase synchrony represented by IH-PSIs provides a novel surrogate marker for clinical status after stroke.

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Background. Motor recovery after stroke is of great clinical interest. Besides magnetic resonance imaging functional connectivity, electroencephalographic synchrony is also an available biomarker. However, the clinical relevance of electroencephalographic synchrony in hemiparesis has not been fully understood. Objective. We aimed to demonstrate the usefulness of the phase synchrony index (PSI) by showing associations between the PSI and poststroke outcome in patients with hemiparesis. Methods. This observational study included 40 participants with cortical ischemic stroke (aged 69.8 ± 13.8 years) and 22 healthy controls (aged 66.9 ± 6.5 years). Nineteen-channel electroencephalography was recorded at 36.9 ± 11.8 days poststroke. Upper extremity Fugl-Meyer scores were assessed at the time of admission/before discharge (FM-UE1/FM-UE2; 32.6 ± 12.3/121.0 ± 44.7 days poststroke). Then, correlations between the PSIs and FM-UE1 as well as impairment reduction after rehabilitation (FM-UEgain) were analyzed. Results. The interhemispheric PSI (alpha band) between the primary motor areas (M1s) was lower in patients than in controls and was selectively correlated with FM-UE1 ( P = .001). In contrast, the PSI (theta band) centered on the contralesional M1 was higher in patients than in controls and was selectively correlated with FM-UEgain ( P = .003). These correlations remained significant after adjusting for confounding factors (age, time poststroke, National Institute of Health Stroke Scale, and lesion volume). Furthermore, the latter correlation was significant in severely impaired patients (FM-UE1 ≤ 10). Conclusions. This study showed that the PSIs were selectively correlated with motor impairment and recovery. Therefore, the PSIs may be potential biomarkers in persons with a hemispheric infarction.