ESCRT-I protein UBAP1 controls ventricular expansion and cortical neurogenesis via modulating adherens junctions of radial glial cells.

Intricate cerebral cortex formation is orchestrated by the precise behavior and division dynamics of radial glial cells (RGCs). Endocytosis functions in the recycling and remodeling of adherens junctions (AJs) in response to changes in RGC activity and function. Here, we show that conditional disruption of ubiquitin-associated protein 1 (UBAP1), a component of endosomal sorting complex required for transport (ESCRT), causes severe brain dysplasia and prenatal ventriculomegaly. UBAP1 depletion disrupts the AJs and polarity of RGCs, leading to failure of apically directed interkinetic nuclear migration. Accordingly, UBAP1 knockout or knockdown results in reduced proliferation and precocious differentiation of neural progenitor cells. Mechanistically, UBAP1 regulates the expression and surface localization of cell adhesion molecules, and ß-catenin over-expression significantly rescues the phenotypes of Ubap1 knockdown in vivo. Our study reveals a critical physiological role of the ESCRT machinery in cortical neurogenesis by regulating AJs of RGCs.

A structured combination of ensemble classifier and filter-based feature selection to improve breast cancer diagnosis.

INTRODUCTION: Advances in technology have led to the emergence of computerized diagnostic systems as intelligent medical assistants. Machine learning approaches cannot replace professional humans, but they can change the treatment of diseases such as cancer and be used as medical assistants. BACKGROUND: Breast cancer treatment can be very effective, especially when the disease is detected in the early stages. Feature selection and classification are common data mining techniques in machine learning that can provide breast cancer diagnosis with high speed, low cost and high precision. METHODOLOGY: This paper proposes a new intelligent approach using an integrated filter-evolutionary search-based feature selection and an optimized ensemble classifier for breast cancer diagnosis. The selected features mainly relate to the viable solution as the selected features are successfully used in the breast cancer disease classification process. The proposed feature selection method selects the most informative features from the original feature set by integrating adaptive thresholder information gain-based feature selection and evolutionary gravity-search-based feature selection. Meanwhile, classification model is done by proposing a new intelligent multi-layer perceptron neural network-based ensemble classifier. RESULTS: The simulation results show that the proposed method provides better performance compared to the state-of-the-art algorithms in terms of various criteria such as accuracy, sensitivity and specificity. Specifically, the proposed method achieves an average accuracy of 99.42% on WBCD, WDBC and WPBC datasets from Wisconsin database with only 56.7% of features. CONCLUSION: Systems based on intelligent medical assistants configured with machine learning approaches are an important step toward helping doctors to detect breast cancer early.

Antisenescence ZIF-8/Resveratrol Nanoformulation with Potential for Enhancement of Bone Fracture Healing in the Elderly.

Accumulation of senescent cells in the elderly impairs bone homeostasis. It is important to alleviate cell senescence and scavenge excessive oxidative stress for enhanced bone fracture healing in elderly patients. In this study, resveratrol (RSV), an antioxidant drug, was encapsulated in a biocompatible zeolitic imidazolate framework-8 (ZIF-8) nanoparticle to protect it from oxidation and improve its bioavailability. Cells responsible for bone healing, including osteoblasts, bone marrow-derived mesenchymal stem cells (BMSCs), macrophages, and endothelial cells, were used to evaluate the regulatory role of the nanoformulation in the alleviation of cellular senescence and promotion of cell functions. It was proved that the nanoformulation sustainably released RSV with well-preserved bioactivity and improved bioavailability. Cell experiments confirmed that ZIF-8/RSV was capable of alleviating the senescence of cells [human osteoblasts (HOBs), BMSCs, H2O2-induced senescent vascular endothelial cells (HUVECs)] and scavenging excessive intracellular reactive oxygen species (ROS). Excitingly, the ZIF-8/RSV improved the osteogenic ability of senescent osteoblasts and promoted macrophage M2 polarization. In addition, the ZIF-8/RSV also enhanced the angiogenic function of senescent HUVECs. More importantly, the ZIF-8/RSV nanoformulation outperformed the REV alone, indicating the critical role of encapsulation using ZIF-8. These findings suggest that the ZIF-8/RSV nanoformulation exhibits potential for bone fracture treatment in elderly patients.

Downregulation of CDC25C in NPCs Disturbed Cortical Neurogenesis.

Cell division regulators play a vital role in neural progenitor cell (NPC) proliferation and differentiation. Cell division cycle 25C (CDC25C) is a member of the CDC25 family of phosphatases which positively regulate cell division by activating cyclin-dependent protein kinases (CDKs). However, mice with the Cdc25c gene knocked out were shown to be viable and lacked the apparent phenotype due to genetic compensation by Cdc25a and/or Cdc25b. Here, we investigate the function of Cdc25c in developing rat brains by knocking down Cdc25c in NPCs using in utero electroporation. Our results indicate that Cdc25c plays an essential role in maintaining the proliferative state of NPCs during cortical development. The knockdown of Cdc25c causes early cell cycle exit and the premature differentiation of NPCs. Our study uncovers a novel role of CDC25C in NPC division and cell fate determination. In addition, our study presents a functional approach to studying the role of genes, which elicit genetic compensation with knockout, in cortical neurogenesis by knocking down in vivo.

Stress-Activated Protein Kinase JNK Modulates Depression-like Behaviors in Mice.

Stress is considered as a major cause of depression. C-Jun N-terminal kinase (JNK) is a member of the stress-induced mitogen activated protein (MAP) kinase family which is often activated through phosphorylation. Clinical studies and animal experiments have found that abnormal phosphorylation/activation of JNK exists in the occurrence of various psychiatric diseases. Recently, several studies linked JNK kinase activity to depression. However, whether excessive activation of JNK activity is directly responsible for the occurrence of depression and the underlying mechanisms remain unclear. Here, we constructed a conditional transgenic mouse which is specifically expressing MKK7-JNK1 (CAJNK1) in the central nervous system. CAJNK1 mice showed activation of JNK and lead to depression-like behavior in mice. Transcriptome analysis indicates reduced expression of synaptic-associated genes in CAJNK1 mice brains. Consistently, we found abnormal dendritic spine development and PSD95 downregulation in CAJNK1 hippocampal neurons. Our studies provide compelling evidence that activation of JNK as an intrinsic factor leading to depression-like behavior in mice provides direct clues for targeting the JNK activity as a potential therapeutic strategy for depression.

Modification of Poly(Ethylene 2,5-Furandicarboxylate) with Poly(Ethylene glycol) for Biodegradable Copolyesters with Good Mechanical Properties and Spinnability.

Using 2,5-furandicarboxylic acid, ethylene glycol, and poly(ethylene glycol) as raw materials and ethylene glycol antimony as a catalyst, poly(ethylene furandicarboxylate) (PEF) and polyethylene glycol (PEG) copolymers (PEGFs) were synthesized by transesterification by changing the molecular weight of PEG (from 600 to 10,000 g/mol) and the PEG content (from 10 to 60 wt %). The thermal, hydrophilic, degradation, and spinnility characteristics of these copolymers were then investigated. Thermogravimetric analysis shows that PEGF is thermally stable at 62 °C, much lower than the temperature for PEF. The intrinsic viscosity of the obtained copolyester was between 0.67 and 0.99 dL/g, which is higher than the viscosity value of PEF. The contact angle experiment shows that the hydrophilicity of PEGFs is improved (the surface contact angle is reduced from 91.9 to 63.3°), which gives PEGFs a certain degradability, and the maximum mass loss can reach approximately 15%. Melt spinning experiments show that the PEGF polymer has poor spinnability, but the mechanical properties of the polymer monofilament are better.