In vivo regulators of neural stem cell development and function

Neural stem cells in the brain give rise to both neurons and glia cells during embryonic development and help maintain tissue homeostasis in adulthood. Although transcription factors and intracellular signaling pathways that modulate NSC function in embryonic and adult brain have been heavily studied, in vivo functions of long noncoding RNAs (lncRNAs) and chromatin regulators in NSCs are still poorly understood. Pnky is a nuclear-enriched lncRNA that is transcribed divergently from the neighboring proneural transcription factor Pou3f2. In the embryonic cortex, I found that Pnky deletion increases neuronal differentiation and depletes NSCs prematurely, resulting in defects in cortical laminar structure in postnatal mice. Pnky expression from a bacterial artificial chromosome (BAC) transgene rescues the in vivo phenotypes of Pnky-deleted brains, supporting the idea that Pnky acts in trans as a key regulator of NSC function and neurogenesis in the embryonic cortex. Chromatin regulator JMJD3 is a histone demethylase implicated in development and disease of multiple organs. My studies show that Jmjd3-deletion in the hippocampus results in depletion of adult NSCs. During development, Jmjd3-deleted dentate gyrus precursors precociously differentiate into neurons, resulting in failed establishment of the hippocampal NSC niche. Single cell RNA-sequencing reveals a broad disruption of genes involved in maintaining stem cell function in Jmjd3-deleted NSCs. In the adult brain, loss of Jmjd3 similarly leads to precocious neuronal differentiation, reflecting the loss of gene expression signatures related to stem cell maintenance. These data indicate both lncRNA-Pnky and JMJD3 may control the rate of neurogenesis, acting like a cell-intrinsic clock for NSCs

Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1

Cancer therapeutics: Extending a drug's reach A new drug that blocks heat shock proteins (HSPs), helper proteins that are co-opted by cancer cells to promote tumor growth, shows promise for cancer treatment. Several drugs have targeted HSPs, since cancer cells are known to hijack these helper proteins to shield themselves from destruction by the body. However, the drugs have had limited success. Hye-Kyung Park and Byoung Heon Kang at Ulsan National Institutes of Science and Technology in South Korea and coworkers noticed that the drugs were not absorbed into mitochondria, a key cellular compartment, and HSPs in this compartment were therefore not being blocked. They identified a new HSP inhibitor that can reach every cellular compartment and inhibit all HSPs. Testing in mice showed that this inhibitor effectively triggered death of tumor cells, and therefore shows promise for anti-cancer therapy. The Hsp90 family proteins Hsp90, Grp94, and TRAP1 are present in the cell cytoplasm, endoplasmic reticulum, and mitochondria, respectively; all play important roles in tumorigenesis by regulating protein homeostasis in response to stress. Thus, simultaneous inhibition of all Hsp90 paralogs is a reasonable strategy for cancer therapy. However, since the existing pan-Hsp90 inhibitor does not accumulate in mitochondria, the potential anticancer activity of pan-Hsp90 inhibition has not yet been fully examined in vivo. Analysis of The Cancer Genome Atlas database revealed that all Hsp90 paralogs were upregulated in prostate cancer. Inactivation of all Hsp90 paralogs induced mitochondrial dysfunction, increased cytosolic calcium, and activated calcineurin. Active calcineurin blocked prosurvival heat shock responses upon Hsp90 inhibition by preventing nuclear translocation of HSF1. The purine scaffold derivative DN401 inhibited all Hsp90 paralogs simultaneously and showed stronger anticancer activity than other Hsp90 inhibitors. Pan-Hsp90 inhibition increased cytotoxicity and suppressed mechanisms that protect cancer cells, suggesting that it is a feasible strategy for the development of potent anticancer drugs. The mitochondria-permeable drug DN401 is a newly identified in vivo pan-Hsp90 inhibitor with potent anticancer activity

Victimization, Urbanicity, and the Relevance of Context: School Routines, Race and Ethnicity, and Adolescent Violence

The United States is undergoing a historical racial and ethnic demographic shift. There is limited criminological research exploring if and how these changes influence variation in the relationship between routine activity theory and adolescent violence. Although the link between routine activities and victimization has been tested and well established, criminologists have questioned if routine activities can explain adolescent violence across different social contexts. Prior research demonstrates that there are potential nuances in the theoretical connections between routine activities and victimization, particularly when considering race and ethnicity. This study builds on previous research by questioning if the elements of routine activities predict victimization across predominately urban, rural, and suburban schools. The implications of the relevance of school context in the relationships between routine activities and adolescent victimization will also be discussed more generally

Robust nodal superconductivity induced by isovalent doping in Ba(Fe1−x_{1-x}Rux_x)2_2As2_2 and BaFe2_2(As1−x_{1-x}Px_x)2_2

We present the ultra-low-temperature heat transport study of iron-based superconductors Ba(Fe$_{1-x}$Ru$_x$)$_2$As$_2$ and BaFe$_2$(As$_{1-x}$P$_x$)$_2$. For optimally doped Ba(Fe$_{0.64}$Ru$_{0.36}$)$_2$As$_2$, a large residual linear term $\kappa_0/T$ at zero field and a $\sqrt{H}$ dependence of $\kappa_0(H)/T$ are observed, which provide strong evidences for nodes in the superconducting gap. This result demonstrates that the isovalent Ru doping can also induce nodal superconductivity, as P does in BaFe$_2$(As$_{0.67}$P$_{0.33}$)$_2$. Furthermore, in underdoped Ba(Fe$_{0.77}$Ru$_{0.23}$)$_2$As$_2$ and heavily underdoped BaFe$_2$(As$_{0.82}$P$_{0.18}$)$_2$, $\kappa_0/T$ manifests similar nodal behavior, which shows the robustness of nodal superconductivity in the underdoped regime and puts constraint on theoretical models.Comment: 5 pages, 4 figures - with two underdoped samples added, this paper supersedes arXiv:1106.541

Chfr is linked to tumour metastasis through the downregulation of HDAC1

Chfr is a ubiquitin ligase that functions in the mitotic checkpoint by delaying entry into metaphase in response to mitotic stress. It has been suggested that Chfr is a tumour suppressor as Chfr is frequently silenced in human cancers. To better understand how Chfr activity relates to cell-cycle progression and tumorigenesis, we sought to identify Chfr-interacting proteins using affinity purification combined with mass spectrometry. Histone deacetylase 1 (HDAC1), which represses transcription by deacetylating histones, was newly isolated as a Chfr-interacting protein. Chfr binds and downregulates HDAC1 by inducing its polyubiquitylation, both in vitro and in vivo. Ectopic expression of Chfr in cancer cells that normally do not express it results in downregulation of HDAC1, leading to upregulation of the Cdk inhibitor p21^(CIP1/WAF1) and the metastasis suppressors KAI1 and E-cadherin. Coincident with these changes, cells arrest in the G1 phase of the cell cycle and become less invasive. Collectively, our data suggest that Chfr functions as a tumour suppressor by regulating HDAC1