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Abstract WWC1 regulates episodic learning and memory, and genetic nucleotide polymorphism of WWC1 is associated with neurodegenerative diseases such as Alzheimer’s disease. However, the molecular mechanism through which WWC1 regulates neuronal function has not been fully elucidated. Here, we show that WWC1 and its paralogs (WWC2/3) bind directly to angiomotin (AMOT) family proteins (Motins), and recruit USP9X to deubiquitinate and stabilize Motins. Deletion of WWC genes in different cell types leads to reduced protein levels of Motins. In mice, neuron-specific deletion of Wwc1 and Wwc2 results in reduced expression of Motins and lower density of dendritic spines in the cortex and hippocampus, in association with impaired cognitive functions such as memory and learning. Interestingly, ectopic expression of AMOT partially rescues the neuronal phenotypes associated with Wwc1/2 deletion. Thus, WWC proteins modulate spinogenesis and cognition, at least in part, by regulating the protein stability of Motins.

Based on the seismic and drilling data, casting thin sections, geochemical analysis of oil and rock samples, and hydrocarbon generation history simulation, the hydrocarbon accumulation characteristics and exploration direction of Termit superimposed marine—continental rift basin are discussed. The Termit basin is superimposed with two-phase rifts (Early Cretaceous and Paleogene). The subsidence curves from two wells on the Trakes slope in the east of the basin show high subsidence rate in the Late Cretaceous, which is believed to be high deposition rate influenced by transgression. However, a weak rift may also be developed. The depositional sequences in the Termit basin were controlled by the Late Cretaceous marine transgression cycle and the Paleogene lacustrine transgression cycle, giving rise to two types of superimposed marine—continental “source-sink” deposits. The marine and continental mixed source rocks developed universally in the whole basinduring the marine transgression period, and are overlaid by the Paleogene Sokor 1 reservoir rocks and Sokor 2 caprocks developed during the lacustrine transgression period, forming the unique superimposed marine—continental basin in WCARS. The early low geothermal gradient in the Termit basin resulted in the late hydrocarbon generated by the source rock of Upper Cretaceous Yogou in Paleogene. Mature source rock of Upper Cretaceous Donga developed in the Trakes slope, so that the double-source-supply hydrocarbon and accumulation models are proposed for the Trakes slope in which formed the oil fields. Due to virtue of the newly proposed hydrocarbon accumulation model and the exploration activities in recent years in the Termit superimposed marine—continental rift basin, an additional effective exploration area of about 2500 km2 has been confirmed in the east of the basin. It is believed that potential domains such as Sokor 1, Donga and Upper Cretaceous lithologic traps in the southeast of the basin are key expected targets for exploration and frontier evaluation in future.

Based on seismic and drilling data in the study area, the geological structure and kinematic process of the Termit rift basin were studied using seismic profile interpretation and balanced restoration to find out the dynamic mechanism of the basin. (1) The geological structure of the Termit Basin is represented as a narrow rift basin, with development of series of structural styles in extensional, extensional strike-slip and compressional stress setting. On plane, it is narrow in the north and wide in the south, and transitions from graben to half-graben from north to south; it features a graben controlled by the boundary faults in the north and a fault-overlapped half-graben in the south. (2) Before the Cretaceous, a series of hidden faults developed in the West African rift system, which laid the foundation for the development location and distribution direction of the Termit Basin; during the Cretaceous to Paleogene periods, the basin experienced two phases of rifting in Early Cretaceous and Paleogene, which controlled the initial structure and current structural shape of the basin respectively; during the Neogene to Quaternary, the basin was subjected to weak transformation. (3) In the Precambrian, the Pan-African movement gave rise to a narrow and long weak zone within the African plate, which provided the pre-existing structural conditions for the formation of the Termit Basin. In the Early Cretaceous, affected by the South Atlantic rifting, the Pan African weak zone was reactivated, resulting in the first stage of rifting and the basic structural framework of the Termit Basin. In the Paleogene, affected by the subduction and convergence of the Neo-Tethys Ocean, the African-Arabian plate extended in near E-W trending, and the Termit Basin experienced the second stage of rifting. The oblique extension in this period caused intense structural differentiation, and the current structural pattern of alternate uplifts and depressions took shape gradually.

Perinatal autopsies are essential to establish the cause of stillbirth or neonatal death and improve clinical practice. Limited studies have provided detailed major missed diagnoses of perinatal deaths in current clinical practice. In this retrospective audit of 177 perinatal autopsies including 99 stillbirths and 78 neonatal deaths with complete pathologic evaluation, 66 cases (21 Class I and 45 Class II diagnostic errors) were revealed as major discrepancies (37.3%), with complete agreements in 80 cases (45.2%). The difference in major discrepancies between stillbirth and neonatal death groups was significant (P

Abstract Background Alteration of DNA methylation is an important event in pathogenesis and progression of hepatocellular carcinoma (HCC). DNA methyltransferase (DNMT) 1, the foremost contributor in DNA methylation machinery, was revealed elevated in HCC and significantly correlates with poor prognosis. However, the transcriptional regulation of DNMT1 in HCC remains unknown. Methods Real‐time PCR and immunohistochemistry were performed to detect DNMT1 and zinc finger transcription factor 191 (ZNF191) expressions in HCCs. Transcription activity of DNMT1promoter was analyzed with Luciferase reporter activity assay. The binding capacity of ZNF191 protein to DNMT1 promoter was examined with chromatin immunoprecipitation‐qPCR (ChIP‐qPCR) and electrophoretic mobility shift assay (EMSA). DNA methylation level of hepatoma cells was detected with Methylation array. Results ZNF191 can regulate DNMT1 mRNA and protein expression positively, and increase the transcription activity of the DNMT1 promoter. ChIP‐qPCR and EMSA revealed that ZNF191 protein directly binds to the DNMT1 promoter at nt‐240 AT(TCAT)3TC. Moreover, DNMT1 and ZNF191 expression correlate positively in human HCCs. With methylation array, DNA methylation alteration was observed in hepatoma cells with ZNF191 knockdown, and the differential methylation sites are enriched in the PI3K‐AKT pathway. Furthermore, we proved DNMT1 contributes the effect of ZNF191 on hepatoma cell growth via the PI3K‐AKT pathway. Conclusion ZNF191 is a novel transcription regulator for DNMT1, and the pro‐proliferation effect of ZNF191/DNMT1/p‐AKT axis in hepatoma cells implies that ZNF191 status in HCCs may affect the therapeutic effect of DNMTs inhibitors and PI3K inhibitors for precise treatment of the disease.

Total internal reflection (TIR) is useful for interrogating physical and chemical processes that occur at the interface between two transparent media. Yet prism-coupled TIR imaging microscopes suffer from limited sensing areas due to the fact that the interface (the object plane) is not perpendicular to the optical axis of the microscope. In this paper, we show that an electrically tunable lens can be used to rapidly and reproducibly correct the focal length of an oblique-incidence scanning microscope (OI-RD) in a prism-coupled TIR geometry. We demonstrate the performance of such a correction by acquiring an image of a protein microarray over a scan area of 4 cm2 with an effective resolution of less than 20 microns. The electronic focal length tuning eliminates the mechanical movement of the illumination lens in the scanning microscope and in turn the noise and background drift associated with the motion.

Velocardiofacial syndrome (VCFS) is a disease in human with an expansive phenotypic spectrum and diverse genetic mechanisms mainly associated with copy number variations (CNVs) on 22q11.2 or other chromosomes. However, the correlations between CNVs and phenotypes remain ambiguous. This study aims to analyze the types and sizes of CNVs in VCFS patients, to define whether correlations exist between CNVs and clinical manifestations in Chinese VCFS patients. In total, 55 clinically suspected Chinese VCFS patients and 100 normal controls were detected by multiplex ligation-dependent probe amplification (MLPA). The data from MLPA and all the detailed clinical features of the objects were documented and analyzed. A total of 44 patients (80.0%) were diagnosed with CNVs on 22q11.2. Among them, 43 (78.2%) presented with 22q11.2 heterozygous deletions, of whom 40 (93.0%) had typical 3-Mb deletion, and 3 (7.0%) exhibited proximal 1.5-Mb deletion; no patient was found with atypical deletion on 22q11.2. One patient (1.8%) presented with a 3-Mb duplication mapping to the typical 3-Mb region on 22q11.2, while none of the chromosomal abnormalities in the MLPA kit were found in the other 11 patients and 100 normal controls. All the 43 patients with 22q11.2 deletions displayed characteristic face and palatal anomalies; 37 of them (86.0%) had cognitive or behavioral disorders, and 23 (53.5%) suffered from immune deficiencies; 10 patients (23.3%) manifested congenital heart diseases. Interestingly, all patients with the characteristic face had 22q11.2 heterozygous deletions, but no difference in phenotypic spectrum was observed between 3-Mb and 1.5-Mb deletions. Our data suggest that the characteristic face can be used as a key indicator for direct diagnosis of 22q11.2 deletions in Chinese VCFS patients.

Small-molecule microarray (SMM) is an effective platform for identifying lead compounds from large collections of small molecules in drug discovery, and efficient immobilization of molecular compounds is a pre-requisite for the success of such a platform. On an isocyanate functionalized surface, we studied the dependence of immobilization efficiency on chemical residues on molecular compounds, terminal residues on isocyanate functionalized surface, lengths of spacer molecules, and post-printing treatment conditions, and we identified a set of optimized conditions that enable us to immobilize small molecules with significantly improved efficiencies, particularly for those molecules with carboxylic acid residues that are known to have low isocyanate reactivity. We fabricated microarrays of 3375 bioactive compounds on isocyanate functionalized glass slides under these optimized conditions and confirmed that immobilization percentage is over 73%.

Background: The purpose of this study is to evaluate the prognostic value of TFPI-2 expression in breast cancer patients through examining the correlation between TFPI-2 expression and breast cancer clinicopathologic features. Methods: Immunohistochemical staining combined with digital image analysis was used to quantify the expression of TFPI-2 protein in breast tumor tissues. For evaluation of the prognostic value of TFPI-2 expression to each clinicopathologic factor, Kaplan-Meier method and COX's Proportional Hazard Model were employed. Results: TFPI-2 expression was significantly correlated with tumor size, lymph node metastasis, histologic grade, clinical stage, and vessel invasion. More importantly, TFPI-2 expression was also associated with disease-free survival (DFS) of breast cancer patients. We found that patients with high TFPI-2 expression had longer DFS compared with those with low or negative expression of TFPI-2 (P <0.05, log-rank test). Cox's regression analysis indicated that TFPI-2 expression, histologic grade, and vessel invasion might be significant prognostic factors for DFS, while TFPI-2 expression and histologic grade were the most significant independent predictors for tumor recurrence. Compared with the group with low/high TFPI-2 expression, the TFPI-2 negative group was more likely to have tumor relapse. The hazard ratio of DFS is 0.316 (P <0.01). Conclusions: Low or negative expression of TFPI-2 is associated with breast cancer progression, recurrence and poor survival outcome after breast cancer surgery. TFPI-2 expression in breast tumors is a potential prognostic tool for breast cancer patients. [ABSTRACT FROM AUTHOR]