Glioblastoma multiform (GBM) is the most common malignant glioma of all the brain tumors and currently effective treatment options are still lacking. GBM is frequently accompanied with overexpression and/or mutation of epidermal growth factor receptor (EGFR), which subsequently leads to activation of many downstream signal pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt/rapamycin-sensitive mTOR-complex (mTOR) pathway. Here we explored the reason why inhibition of the pathway may serve as a compelling therapeutic target for the disease, and provided an update data of EFGR and PI3K/Akt/mTOR inhibitors in clinical trials.

Myeloid differentiation protein-88 (MyD88) is a signal adaptor protein required for cytokine production following engagement of Toll-like receptors (TLRs) by their cognate ligands. Activation of both TLR-3 and TLR-4, however, can engage signaling events independent of MyD88 expression. The relative importance of these MyD88-dependent and -independent signaling pathways in the macrophage response to lipopolysaccharide (LPS) is unknown. Here we define these events using microarray expression profiling of LPS-stimulated macrophages taken from MyD88-null and wild-type mice. Of the 1,055 genes found to be LPS responsive, only 21.5% were dependent on MyD88 expression, with MyD88-independent genes constituting 74.7% of the genetic response. This MyD88-independent gene expression was predominantly transcriptionally regulated, as it was unaffected by cycloheximide blockade of new protein synthesis. A previously undescribed group of LPS-regulated genes (3.8%), whose induction or repression was significantly greater in the absence of MyD88, was also identified by these studies. The regulation of these genes suggested that MyD88 could serve as a molecular brake, constraining gene activity in a subset of LPS-responsive genes. The findings generated with LPS stimulation were recapitulated by exposure of macrophages to live Escherichia coli. These expression-profiling studies redefine the current dogma of TLR-4 signaling and establish that MyD88, although essential for some of the best-characterized macrophage responses to LPS, is not required for the regulation of the majority of genes engaged by macrophage exposure to endotoxin or live bacteria.

The crux for solar N2 reduction to ammonia is activating N2 into its high-energy intermediate. Applying a simultaneous multi-electron reduction process could avoid intermediate generation and decrease the thermodynamic barrier. However, this process is extremely difficult from a kinetic view and experiments so far have not shown it is accessible. Here we show the first direct evidence of trion induced multi-electron N2 reduction on ultrathin MoS2. By applying light induced trions, N2 molecular was activated and transformed into ammonia by a simultaneous six-electron reduction process, with a high ammonia synthesis rate of 325 mol/g h without the assistant of any organic scavengers or co-catalyst. Bulk MoS2 without trions did not exhibit any activity. This demonstrates multi-electron reduction may be realized in electron-rich semiconductors with high concentration of localized electrons such as trions. The methodology of simultaneous multi-electron reduction has wide implications for reactions beyond N2 reduction and for materials beyond MoS2. .

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Macrophage polarization plays a critical role in tissue homeostasis, disease pathogenesis, and inflammation and its resolution. IL-4-induced macrophage polarization involves induction of STAT6 and KLF4 that induce each other and promote M2 polarization. However, how these transcription factors implement M2 polarization is not understood. We report that in murine macrophages MCPIP, induced by KLF4, inhibits M1 polarization by inhibiting NF-κB activation and implements M2 polarization using both its deubiquitinase and RNase activities that cause sequential induction of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress and autophagy required for M2 polarization. MCPIP also induces C/EBPβ and PPARγ that promote M2 polarization. Macrophages from mice with myeloid-targeted overexpression of MCPIP show elevated expression of M2 markers and reduced response to LPS, whereas macrophages from mice with myeloid-specific deletion of MCPIP manifest elevated M1 polarization with enhanced phagocytic activity. Thus, both in vivo and in vitro experiments demonstrate that the transcription factors STAT6 and KLF4 implement IL-4-induced M2 polarization via the dual catalytic activities of MCPIP.

MicroRNAs (miRNAs) are members of a growing family of non-coding transcripts, 21-23 nucleotides long, which regulate a diverse collection of biological processes and various diseases by RNA-mediated gene-silencing mechanisms. While currently many studies focus on defining the regulatory functions of miRNAs, few are directed towards how miRNA genes are themselves transcriptionally regulated. Recent studies of miRNA transcription have elucidated RNA polymerase II as the major polymerase of miRNAs, however, little is known of the structural features of miRNA promoters, especially those of mammalian miRNAs. Here, we review the current literature regarding features conserved among miRNA promoters useful for their detection and the current novel methodologies available to enable researchers to advance our understanding of the transcriptional regulation of miRNA genes.

Nanohydroxyapatite (HA) synthesized by biomimetic strategy is a promising nanomaterial as bone substitute due to its physicochemical features similar to those of natural nanocrystal in bone tissue. Inspired by mussel adhesive chemistry, a novel nano-HA was synthesized in our work by employing polydopamine (pDA) as template under weak alkaline condition. Subsequently, the as-prepared pDA-templated HA (tHA) was introduced into polycaprolactone (PCL) matrix via coelectrospinning, and a bioactive tHA/PCL composite nanofiber scaffold was developed targeted at bone regeneration application. Our research showed that tHA reinforced PCL composite nanofibers exhibited favorable cytocompatibility at given concentration of tHA (0-10 w.t%). Compared to pure PCL and traditional nano-HA enriched PCL (HA/PCL) composite nanofibers, enhanced cell adhesion, spreading and proliferation of human mesenchymal stem cells (hMSCs) were observed on tHA/PCL composite nanofibers on account of the contribution of pDA present in tHA. More importantly, tHA nanoparticles exposed on the surface of composite nanofibers could further promote osteogenesis of hMSCs in vitro even in the absence of osteogenesis soluble inducing factors when compared to traditional HA/PCL scaffolds, which was supported by in vivo test as well according to the histological analysis. Overall, our study demonstrated that the developed tHA/PCL composite nanofibers with enhanced cytocompatibility and osteogenic capacity hold great potential as scaffolds for bone tissue engineering.

Motivation: The identification of microRNA (miRNA) target sites is fundamentally important for studying gene regulation. There are dozens of computational methods available for miRNA target site prediction. Despite their existence, we still cannot reliably identify miRNA target sites, partially due to our limited understanding of the characteristics of miRNA target sites. The recently published CLASH (crosslinking ligation and sequencing of hybrids) data provide an unprecedented opportunity to study the characteristics of miRNA target sites and improve miRNA target site prediction methods.Results: Applying four different machine learning approaches to the CLASH data, we identified seven new features of miRNA target sites. Combining these new features with those commonly used by existing miRNA target prediction algorithms, we developed an approach called TarPmiR for miRNA target site prediction. Testing on two human and one mouse non-CLASH datasets, we showed that TarPmiR predicted more than 74.2% of true miRNA target sites in each dataset. Compared with three existing approaches, we demonstrated that TarPmiR is superior to these existing approaches in terms of better recall and better precision.Availability and Implementation: The TarPmiR software is freely available at http://hulab.ucf.edu/research/projects/miRNA/TarPmiR/.Contacts: haihu@cs.ucf.edu or xiaoman@mail.ucf.eduSupplementary information: Supplementary data are available at Bioinformatics online.