Functional and Structural Connectivity of the Cerebellar Nuclei With the Striatum and Cerebral Cortex in First-Episode Psychosis.

OBJECTIVE: Evidence suggests that the cortico-striatal-thalamo-cortical circuitry plays an important role in schizophrenia pathophysiology. Cerebellar contribution from deep cerebellar nuclei to the circuitry has not yet been examined. The authors investigated resting-state functional connectivity (RSFC) of cerebellar output nuclei with striatal-thalamic-cortical regions in relation to white-matter integrity and regional gray-matter volumes in first-episode psychosis (FEP). Methods: Forty FEP patients and 40 age- and gender-matched healthy control subjects (HCs) participated. RSFC between cerebellar nuclei and striatal-thalamic-cortical regions was examined. Diffusion tensor imaging and volumetric scans were examined for possible structural constraints on RSFC. The authors also examined relationships between neuroimaging variables and cognitive and clinical measures. Results: FEP patients, compared with HCs, exhibited decreased RSFC between the left fastigial nucleus and right putamen, which was associated with poor letter fluency performance and lower global assessment of functioning scores. By contrast, patients showed widespread increased accumbens network connectivity in the left nucleus. The authors further observed both hypo- and hyper-RSFC between the cerebellar nuclei and fronto-parietal areas in patients, independent of striatal activity. Finally, the authors found impaired integrity of the left superior cerebellar peduncle and decreased bilateral putamen volume in patients, whereas structural-functional relationships found in HCs were absent in patients. Conclusions: This study provides evidence of disordered RSFC of cerebellar output nuclei to the striatum and neocortex at the early stage of schizophrenia. Furthermore, dysfunctional cerebellar influences on fronto-parietal areas that are independent of striatal dysfunction in patients with FEP were observed. The results suggest that cortico-striatal abnormalities in patients with FEP are produced by abnormal cerebellar influences.

An ESIPT fluorescent probe and a nanofiber platform for selective and sensitive detection of a nerve gas mimic.

An ESIPT based fluorescent probe, containing a hydroxyphenyl-benzothiazole fluorophore and an oxime reaction site, serves as a selective probe for a nerve gas mimic, diethyl cyanophosphonate (DECP), in solutions and the gas phase. The probe exhibits more than a 60-fold fluorescence enhancement in the presence of the target, has a limit of detection of 1.3 nM and displays high selectivity toward DECP over closely related substances, including sulfur mustard stimulants and other nerve agent mimics. Moreover, composite nanofibers with relatively low concentrations of the probe (0.45% w/w) exhibit distinct color and fluorescence changes upon exposure to DECP vapor.

Cerebellar Structural Abnormalities Associated With Cognitive Function in Patients With First-Episode Psychosis.

Introduction: The fundamental role of the cerebellum in higher cognitive processing has recently been highlighted. However, inconsistent findings exist in schizophrenia with respect to the exact nature of cerebellar structural abnormalities and their associations with cognitive and clinical features. Materials and Methods: We undertook a detailed investigation of cerebellar lobular volumes in 40 patients with first-episode psychosis (FEP) and 40 healthy controls (HCs) using the spatially unbiased atlas template of the cerebellum (SUIT). We examined the functional significance of cerebellar structural abnormalities in relation to cognitive and clinical outcomes in patients. Results: We found that left cerebellar lobules VI and X volumes were lower in FEP patients, compared to HCs. Smaller left lobules VI and X volumes were associated with fewer number of categories completed on the Wisconsin Card Sorting Test (WCST) in patients. In addition, smaller left lobule X volume was related to performance delay on the Trail Making Test (TMT) Part B in patients. Conclusion: Our results demonstrate that cerebellar structural abnormalities are present at the early stage of schizophrenia. We suggest functional associations of cerebellar structural changes with non-verbal executive dysfunctions in FEP.

Ternary Organic Photovoltaics Prepared by Sequential Deposition of Single Donor and Binary Acceptors.

Binary organic photovoltaics (OPVs) fabricated by single-step (SS) deposition of a binary blend of polymer (or small molecule) donor and fullerene acceptor (SS binary OPV) are widely utilized. To improve the OPV performance, SS ternary OPVs utilizing a ternary blend consisting of two (or one) electron donor(s) and one (or two) electron acceptor(s) have been studied. SS ternary OPVs require more sensitive and complex optimization processes to optimize bulk heterojunctions with bicontinuous nanoscale phase separation of the donor and acceptor. We demonstrated a novel ternary OPV fabricated by sequential (SQ) deposition of a single polymer donor and a binary mixture consisting of a phenyl-C71-butyric acid methyl ester (PCBM) and nonfullerene acceptor, 3,9-bis(2-methylene-(3-(1,1-dicyanomethylene)-indanone))-5,5,11,11-tetrakis(4-hexylphenyl)-dithieno[2,3- d:2,3'- d']- s-indaceno[1,2- b:5,6- b']dithiophene (ITIC). In the SQ ternary OPV, PCBM effectively created a bicontinuous pathway for charge transport with a polymer, and ITIC mainly enhanced light absorption and photovoltage. This complementary effect was not observed in an SS ternary OPV utilizing the same donor and acceptors. Due to these complementary effects, the SQ ternary OPV exhibited a power conversion efficiency of 6.22%, which was 52 and 37% higher than that of the SQ binary OPV and the SS ternary OPV, respectively. In addition, the thermal stability of the SQ ternary OPV was found to be superior to that of the SS ternary OPV.

Critical roles of Cyclin D1 in mouse embryonic fibroblast cell reprogramming.

Although pluripotent stem cells hold great promise in the fields of human disease modeling and regenerative medicine, the molecular basis of Oct-4, Sox2, Klf4, and c-Myc (OSKM)-induced cellular reprogramming remains unclear. To investigate the molecular mechanisms involved in cellular reprogramming, we studied the immediate effects of expression of the OSKM reprogramming factors on mouse embryonic fibroblasts (MEFs) in this study. Induction of the OSKM reprogramming factors significantly altered primary MEF growth properties. Although MEFs not expressing the reprogramming factors underwent replicative senescence within 9-12 days in culture, MEFs expressing the four reprogramming factors proliferated continuously throughout the duration of the experiment, suggesting that the expression of the OSKM reprogramming factors inhibits or delays replicative senescence. Cell cycle progression by the reprogramming factors was accompanied by the accumulation of Cyclin D1 through the early stages of reprogramming in MEFs, leading us to hypothesize that it might play a positive role in cellular reprogramming. Consistent with this hypothesis, forced Cyclin D1 expression enhanced reprogramming if administered concomitant with expression of the OSKM reprogramming factors. Most importantly, unlike wild-type MEFs expressing reprogramming factors, the number of emerging alkaline phosphatase-positive cyclin D1-null colonies was significantly reduced and cyclin D1-null MEFs were unable to initiate mesenchymal-to-epithelial transition. Our studies demonstrate that cyclin D1 is an essential gene in the reprogramming process and that activation of cyclin D1 by reprogramming factors is an important process for somatic cell reprogramming.

The reprogramming factor nuclear receptor subfamily 5, group A, member 2 cannot replace octamer-binding transcription factor 4 function in the self-renewal of embryonic stem cells.

Although octamer-binding transcription factor 4 (Oct-4) is one of the most intensively studied factors in mammalian development, no cellular genes capable of replacing Oct-4 function in embryonic stem (ES) cells have been found. Recent data show that nuclear receptor subfamily 5, group A, member 2 (Nr5a2) is able to replace Oct-4 function in the reprogramming process; however, it is unclear whether Nr5a2 can replace Oct-4 function in ES cells. In this study, the ability of Nr5a2 to maintain self-renewal and pluripotency in ES cells was investigated. Nr5a2 localized to the nucleus in ES cells, similarly to Oct-4. However, expression of Nr5a2 failed to rescue the stem cell phenotype or to maintain the self-renewal ability of ES cells. Furthermore, as compared with Oct-4-expressing ES cells, Nr5a2-expressing ES cells showed a reduced number of cells in S-phase, did not expand normally, and did not remain in an undifferentiated state. Ectopic expression of Nr5a2 in ES cells was not able to activate transcription of ES cell-specific genes, and gene expression profiling demonstrated differences between Nr5a2-expressing and Oct-4-expressing ES cells. In addition, Nr5a2-expressing ES cells were not able to form teratomas in nude mice. Taken together, these results strongly suggest that the gene regulation properties of Nr5a2 and Oct-4 and their abilities to confer self-renewal and pluripotency of ES cells differ. The present study provides strong evidence that Nr5a2 cannot replace Oct-4 function in ES cells.

Frameshift mutations of axon guidance genes ROBO1 and ROBO2 in gastric and colorectal cancers with microsatellite instability.

AIMS: Several lines of evidence indicate that axon guidance genes are involved not only in neural development but also in cancer development. ROBO1 and ROBO2, crucial regulators of axon guidance, are considered potential tumour suppressor genes. The aim of this study was to explore whether ROBO1 and ROBO2 genes are somatically mutated and expressionally altered in gastric (GC) and colorectal cancers (CRC). METHODS: In a public database, we observed that both ROBO1 and ROBO2 had mononucleotide repeats in their coding exons that could be mutation targets in cancers with microsatellite instability (MSI). We analysed mutations of these repeats in 77 GC and 88 CRC either with high MSI (MSI-H) or low MSI/microsatellite stability (MSI-L/MSS) by single-strand conformation polymorphism (SSCP) and DNA sequencing. We analysed ROBO1 and ROBO2 expressions in GC and CRC by immunohistochemistry as well. RESULTS: Overall, we found five ROBO1 and five ROBO2 frameshift mutations in the repeats. They were detected exclusively in the cancers with MSI-H (10/70, 14.2%), but not in MSI-L/MSS (0/95, 0%) (p=0.018). In the immunohistochemistry, loss of ROBO2 expression was identified in 22 (29%) and 17 (19%) of GC and CRC, respectively, while increased expression of ROBO2 was found in 15 (20%) and 22 (25%) of GC and CRC, respectively. There were co-occurrences of mutation and loss of expression in both ROBO1 (4/5, 80% mutated cases, p<0.001) and ROBO2 (5/5, 100% mutated cases, p<0.05) genes. CONCLUSION: This is the first report of ROBO1 and ROBO2 frameshift mutations in GC and CRC. Frameshift mutations of ROBO1 and ROBO2 genes and alteration of ROBO2 expression in GC and CRC suggest that both genes might play roles in the pathogenesis of GC and CRC.

Docosahexaenoic acid induces autophagy through p53/AMPK/mTOR signaling and promotes apoptosis in human cancer cells harboring wild-type p53.

Docosahexaenoic acid (DHA) has been reported to induce tumor cell death by apoptosis. However, little is known about the effects of DHA on autophagy, another complex well-programmed process characterized by the sequestration of cytoplasmic material within autophagosomes. Here, we show that DHA increased both the level of microtubule-associated protein light-chain 3 and the number of autophagic vacuoles without impairing autophagic vesicle turnover, indicating that DHA induces not only apoptosis but also autophagy. We also observed that DHA-induced autophagy was accompanied by p53 loss. Inhibition of p53 increased DHA-induced autophagy and prevention of p53 degradation significantly led to the attenuation of DHA-induced autophagy, suggesting that DHA-induced autophagy is mediated by p53. Further experiments showed that the mechanism of DHA-induced autophagy associated with p53 attenuation involved an increase in the active form of AMP-activated protein kinase and a decrease in the activity of mammalian target of rapamycin. In addition, compelling evidence for the interplay between autophagy and apoptosis induced by DHA is supported by the findings that autophagy inhibition suppressed apoptosis and further autophagy induction enhanced apoptosis in response to DHA treatment. Overall, our results demonstrate that autophagy contributes to the cytotoxicity of DHA in cancer cells harboring wild-type p53.