TBR2 coordinates neurogenesis expansion and precise microcircuit organization via Protocadherin 19 in the mammalian cortex.

Cerebral cortex expansion is a hallmark of mammalian brain evolution; yet, how increased neurogenesis is coordinated with structural and functional development remains largely unclear. The T-box protein TBR2/EOMES is preferentially enriched in intermediate progenitors and supports cortical neurogenesis expansion. Here we show that TBR2 regulates fine-scale spatial and circuit organization of excitatory neurons in addition to enhancing neurogenesis in the mouse cortex. TBR2 removal leads to a significant reduction in neuronal, but not glial, output of individual radial glial progenitors as revealed by mosaic analysis with double markers. Moreover, in the absence of TBR2, clonally related excitatory neurons become more laterally dispersed and their preferential synapse development is impaired. Interestingly, TBR2 directly regulates the expression of Protocadherin 19 (PCDH19), and simultaneous PCDH19 expression rescues neurogenesis and neuronal organization defects caused by TBR2 removal. Together, these results suggest that TBR2 coordinates neurogenesis expansion and precise microcircuit assembly via PCDH19 in the mammalian cortex

Integrated Profiling of MicroRNAs and mRNAs: MicroRNAs Located on Xq27.3 Associate with Clear Cell Renal Cell Carcinoma

Background: With the advent of second-generation sequencing, the expression of gene transcripts can be digitally measured with high accuracy. The purpose of this study was to systematically profile the expression of both mRNA and miRNA genes in clear cell renal cell carcinoma (ccRCC) using massively parallel sequencing technology. Methodology: The expression of mRNAs and miRNAs were analyzed in tumor tissues and matched normal adjacent tissues obtained from 10 ccRCC patients without distant metastases. In a prevalence screen, some of the most interesting results were validated in a large cohort of ccRCC patients. Principal Findings: A total of 404 miRNAs and 9,799 mRNAs were detected to be differentially expressed in the 10 ccRCC patients. We also identified 56 novel miRNA candidates in at least two samples. In addition to confirming that canonical cancer genes and miRNAs (including VEGFA, DUSP9 and ERBB4; miR-210, miR-184 and miR-206) play pivotal roles in ccRCC development, promising novel candidates (such as PNCK and miR-122) without previous annotation in ccRCC carcinogenesis were also discovered in this study. Pathways controlling cell fates (e. g., cell cycle and apoptosis pathways) and cell communication (e. g., focal adhesion and ECM-receptor interaction) were found to be significantly more likely to be disrupted in ccRCC. Additionally, the results of the prevalence screen revealed that the expression of a miRNA gene cluster located on Xq27.3 was consistently downregulated in at least 76.7% of similar to 50 ccRCC patients. Conclusions: Our study provided a two-dimensional map of the mRNA and miRNA expression profiles of ccRCC using deep sequencing technology. Our results indicate that the phenotypic status of ccRCC is characterized by a loss of normal renal function, downregulation of metabolic genes, and upregulation of many signal transduction genes in key pathways. Furthermore, it can be concluded that downregulation of miRNA genes clustered on Xq27.3 is associated with ccRCC

Behavior and lineage progression of neural progenitors in the mammalian cortex.

The cerebral cortex is a central structure in the mammalian brain that enables higher cognitive functions and intellectual skills. It is the hallmark of the mammalian nervous system with enormous complexity, consisting of a large number of neurons and glia that are diverse in morphology, molecular expression, biophysical properties, circuit connectivity and physiological function. Cortical neurons and glia are generated by neural progenitor cells during development. Ensuring the correct cell cycle kinetics, fate behavior and lineage progression of neural progenitor cells is essential to determine the number and types of neurons and glia in the cerebral cortex, which together constitute neural circuits for brain function. In this review, we discuss recent findings on mammalian cortical progenitor cell types and their lineage behaviors in generating neurons and glia, cortical evolution and expansion, and advances in brain organoid technology that allow the modeling of human cortical development under normal and disease conditions.Royal Society Wellcome Trus

Screening wave conditions for the occurrence of green water events on sailing ships

Design loads for extreme wave events on ships, such as slamming and green water, are hard to define. These events depend on details in the incoming waves, ship motions and structure layout, which requires high-fidelity tools such as CFD or experiments to obtain the correct loads. These tools (presently) do not have the capability to fully resolve the long-term statistics of rare events in all metocean conditions over the ship's lifetime. The idea of ‘screening’ is to use lower-fidelity numerical methods to identify the occurrence of extreme load events based on an indicator. A good indicator has a strong correlation to the design load, but is easier to calculate. A high-fidelity tool can then be used to find the loads in these events. The low-fidelity statistics and the high-fidelity loads can be combined to define a design load and its probability. The present study compares different numerical screening indicators for green water loads on a containership against experiments. The quality of the identification of the critical events and the required computational time served as comparison metrics. This showed that screening both with potential flow tools and with coarse mesh CFD tools is feasible, provided the indicator, grid, time step and wave input settings are well chosen. The results from coarse mesh CFD are slightly better than from potential flow, but the computational costs are much higher. The results also show that the peaks and steepness of the relative wave elevation around the bow are suitable green water load indicators, as well as the undisturbed wave crests at the bow. Fine mesh CFD calculations were done for the identified events based on an example indicator, which resulted in a green water load distribution very close to that of the experiments. This study shows that screening could potentially reduce the required high-fidelity modelling time with up to ∼90% compared to common practice.Ship Hydromechanics and Structure

Distinct progenitor behavior underlying neocortical gliogenesis related to tumorigenesis.

Radial glial progenitors (RGPs) give rise to the vast majority of neurons and glia in the neocortex. Although RGP behavior and progressive generation of neocortical neurons have been delineated, the exact process of neocortical gliogenesis remains elusive. Here, we report the precise progenitor behavior and gliogenesis program at single-cell resolution in the mouse neocortex. Fractions of dorsal RGPs transition from neurogenesis to gliogenesis progressively, producing astrocytes, oligodendrocytes, or both in well-defined propensities of ∼60%, 15%, and 25%, respectively, by fate-restricted "intermediate" precursor cells (IPCs). Although the total number of IPCs generated by individual RGPs appears stochastic, the output of individual IPCs exhibit clear patterns in number and subtype and form discrete local subclusters. Clonal loss of tumor suppressor Neurofibromatosis type 1 leads to excessive production of glia selectively, especially oligodendrocyte precursor cells. These results quantitatively delineate the cellular program of neocortical gliogenesis and suggest the cellular and lineage origin of primary brain tumor.Royal Societ

Regulating Phosphorescence Lifetime of Organic Cocrystals by Alkyl Engineering

Phosphorescent cocrystal is one of the emerging room-temperature phosphorescence (RTP) materials. However, it remains a great challenge to understand the relationship between the phosphorescent properties and molecular aggregation. Herein, we prepared a series of organic cocrystals with RTP features composed of different alkyl chain lengths. It is worth noting that the phosphorescent lifetime varied by the different lengths of alkyl chains. For melamine–succinic acid cocrystal, the phosphorescence lifetime can reach up to 512 ms. From the single-crystal analysis, the longer lifetime was mainly attributed to the shorter distance of molecular stacking between phosphorescent chromophores resulting in smaller free volume. This study not only provides a simple method to prepare RTP materials but also explores the relationship between phosphorescent properties and molecular stacking in organic phosphorescent cocrystals