The accuracy of sequence‐based tertiary contact predictions was assessed in a blind prediction experiment at the CASP13 meeting. After 4 years of significant improvements in prediction accuracy, another dramatic advance has taken place since CASP12 was held 2 years ago. The precision of predicting the top L/5 contacts in the free modeling category, where L is the corresponding length of the protein in residues, has exceeded 70%. As a comparison, the best‐performing group at CASP12 with a 47% precision would have finished below the top 1/3 of the CASP13 groups. Extensively trained deep neural network approaches dominate the top performing algorithms, which appear to efficiently integrate information on coevolving residues and interacting fragments or possibly utilize memories of sequence similarities and sometimes can deliver accurate results even in the absence of virtually any target specific evolutionary information. If the current performance is evaluated by F‐score on L contacts, it stands around 24% right now, which, despite the tremendous impact and advance in improving its utility for structure modeling, also suggests that there is much room left for further improvement.

Migration of human glioma cells (hGCs) within the brain parenchyma makes glioblastoma one of the most aggressive and lethal tumors. Studies of the cellular and molecular mechanisms underlying hGC migration are hindered by the limitations of existing glioma models. Here we developed a dorsal root ganglion axon-oligodendrocyte-hGC co-culture to study in real time the migration and interaction of hGCs with their microenvironment. hGCs interact with myelinated and non-myelinated axons through the formation of pseudopodia. Isolation of pseudopodia-localized polysome-bound RNA reveals transcripts of Lck, Paxillin, Crk-II , and Rac1 that undergo local translation. Inhibition of Lck phosphorylation using a small-molecule inhibitor (Lck-I), blocks the phosphorylation of Paxillin and Crk-II, the formation of pseudopodia and the migration of hGCs. In vivo intraventricular administration of the Lck-I using an orthotopic xenograft glioma model, results in statistically significant inhibition of tumor size and significant down-regulation of Nanog-targeted genes, which are associated with glioblastoma patient survival. Moreover, treatment of human glioma stem cells (hGSCs) with Lck-I, results in significant inhibition of self-renewal and tumor-sphere formation. The involvement of Lck in different levels of glioma malignant progression, such as migration, tumor growth, and regulation of cancer stemness, makes Lck a potentially important therapeutic target for human glioblastomas.

Nuc‐ErbB3 an alternative transcript from the ErbB3 locus binds to a specific DNA motif and associates with Schwann cell chromatin. Here we generated a nuc‐ErbB3 knockin mouse that lacks nuc‐ErbB3 expression in the nucleus without affecting the neuregulin‐ErbB3 receptor signaling. Nuc‐ErbB3 knockin mice exhibit hypermyelination and aberrant myelination at the paranodal region. This phenotype is attributed to de‐repression of myelination associated gene transcription following loss of nuc‐ErbB3 and histone H3K27me3 promoter occupancy. Nuc‐ErbB3 knockin mice exhibit reduced association of H3K27me3 with myelination‐associated gene promoters and increased RNA Pol‐II rate of transcription of these genes. In addition, nuc‐ErbB3 directly regulates levels of H3K27me3 in Schwann cells. Nuc‐ErbB3 knockin mice exhibit significant decrease of histone H3K27me3 methyltransferase (HMT) activity and reduced levels of H3K27me3. Collectively, nuc‐ErbB3 is a master transcriptional repressor, which regulates HMT activity to establish a repressive chromatin landscape on promoters of genes during peripheral myelination. GLIA 2016;64:977–992

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The insulin receptor (IR) is an evolutionarily conserved signaling protein that regulates development and cellular metabolism. IR signaling regulates neurogenesis in Drosophila; however, a specific role for the IR in maintaining adult neural stem cells (NSCs) in mammals has not been investigated. We show that conditionally deleting the IR reduces adult NSCs of the subventricular zone by ~70% accompanied by a corresponding increase in progenitors. IR deletion produced hyposmia due to aberrant olfactory bulb neurogenesis. Interestingly, hippocampal neurogenesis was not perturbed nor were hippocampal dependent behaviors.Highly aggressive proneural and mesenchymal glioblastomas (GBMs) had high IR/insulin-like growth factor (IGF) pathway gene expression, and isolated glioma stem cells had an aberrantly high ratio of IR:IGF1R receptors. Moreover, IR knockdown inhibited proneural and mesenchymal GBM tumorsphere growth. Altogether, these data demonstrate that the IR is essential for a subset of normal NSCs as well as for brain tumor cancer stem cell self-renewal.

Cell‐surface‐anchored immunoglobulin superfamily (IgSF) proteins are widespread throughout the human proteome, forming crucial components of diverse biological processes including immunity, cell‐cell adhesion, and carcinogenesis. IgSF proteins generally function through protein‐protein interactions carried out between extracellular, membrane‐bound proteins on adjacent cells, known as trans‐binding interfaces. These protein‐protein interactions constitute a class of pharmaceutical targets important in the treatment of autoimmune diseases, chronic infections, and cancer. A molecular‐level understanding of IgSF protein‐protein interactions would greatly benefit further drug development. A critical step toward this goal is the reliable identification of IgSF trans‐binding interfaces. We propose a novel combination of structure and sequence information to identify trans‐binding interfaces in IgSF proteins. We developed a structure‐based binding interface prediction approach that can identify broad regions of the protein surface that encompass the binding interfaces and suggests that IgSF proteins possess binding supersites. These interfaces could theoretically be pinpointed using sequence‐based conservation analysis, with performance approaching the theoretical upper limit of binding interface prediction accuracy, but achieving this in practice is limited by the current ability to identify an appropriate multiple sequence alignment for conservation analysis. However, an important contribution of combining the two orthogonal methods is that agreement between these approaches can estimate the reliability of the predictions. This approach was benchmarked on the set of 22 IgSF proteins with experimentally solved structures in complex with their ligands. Additionally, we provide structure‐based predictions and reliability scores for the 62 IgSF proteins with known structure but yet uncharacterized binding interfaces.

Glioblastoma (GBM) is one of the most aggressive human tumors. Recent studies have shown that GBM “aggressiveness” is mainly due to populations of glioma stem cells (GSCs) within the tumor mass, which exhibit high migratory potential [3–5], form secondary tumors and can resist chemotherapy and radiation [6]. GSCs exhibit remarkable plasticity, are able to transition between immature and differentiated stages as well as reversibly express various phenotypic markers depending on the tumor microenvironment [7, 8]. Given such challenging features, GSCs have been subject of extensive research. YKL-40 (or Chitinase 3-like1) is a secreted glycoprotein normally expressed by numerous cell types including neutrophils and macrophages [11]. YKL-40 is highly expressed in numerous types of cancer such as breast, colon, lung, ovary, prostate, rectum and GBM [12–15]. RNA-seq on patient-derived GBMs and TCGA database analysis, showed that YKL-40 is one of the highest expressed genes in GBM. YKL-40 expression is associated with the invasiveness, therapy resistance and low survival rate of patients [16]. Here, we aim to elucidate the mechanistic function of YKL-40 in the microenvironment of human glioblastomas and determine its role as a new therapeutic target. We hypothesize that YKL-40 regulates transitions of GSCs phenotypes that underlie glioblastoma invasiveness and aggression. Our preliminary data show that incubation of patient-derived GSCs with YKL-40 induces a marked phenotypic change of GSCs from CD133+/Sox2+ to CD44+/YKL40+. We also performed RNA-seq and ATAC-seq to study the role of YKL-40 in gene expression and chromatin accessibility and identified the YKL-40-modulated transcriptional regulatory network that drives the phenotypic “switch” of GSCs. Finally, we used a novel humanized monoclonal antibody against YKL-40 to treat orthotopic glioblastoma xenografts and show significant reduction of tumor volume. Our work implicates YKL-40 as a microenvironment modulator of GSC phenotypic transitions and demonstrates pre-clinical efficacy of targeting YKL-40 to reduce tumor burden.

treatments comprising different levels of benefits and risks. The DCE was pilot tested and refined through interviews with 5 patients to ensure that the attributes and levels were understood. Attributes and levels in the final DCE included OS (30-90 months in 5-month increments), duration of remission (15-75 months in 5-month increments), risk of a major cardiovascular (CV) event (0%, 25%, 50%), and risk of myelosuppression (0%, 50%, 100%). Preferences for attributes were analysed using a linearly coded multinomial logit model and are expressed as marginal utilities.Results: The DCE was completed by 201 patients. Mean age was 44.8 ± 12.9 years, 67% had at least a college education. At completion of the DCE, 17% had ≥2 relapses, 58% were diagnosed >12 months previously, and 67% were in remission. The most common current treatments were dasatinib (24%) and imatinib (18%). Internal validity was high: 94% of participants had high health numeracy, 84% had high health literacy, 78% passed the choice stability test, 88% passed the choice dominance test, 98% never selected the same option, 96% did not display dominated decision-making, and 96% had an adequate response time. When selecting a preferred treatment, patients placed the most weight on a 1-month increase in OS (0.032 [0.021-0.042]) and a 1-month increase in duration of remission (0.017 [0.012-0.023]) and less weight on reducing the risk of a major CV event by 1% (0.011 [0.008-0.013]) and reducing the risk of myelosuppression by 1% (0.009 [0.008-0.010]). Participants would be willing to tolerate an increase in the risk of a major CV event of 2.9% (1.78-4.02) for 1 additional month of OS and 1.59% (0.95%-2.24%) for an additional 1 month in remission.Conclusions: This study identified the weights that patients attach to treatment characteristics when choosing between TKI-chemotherapy combinations. This insight can inform shared decision-making between patients and their healthcare providers. Further research will focus on understanding variation in preferences between patients.