227 research outputs found
Cancer immunotherapy based on MUSIC platform and STING activation in brain cancer cells
https://openworks.mdanderson.org/sumexp23/1008/thumbnail.jp
Utilizing CD24 as an indicator for tumor aggressiveness and metastasis
https://openworks.mdanderson.org/sumexp23/1020/thumbnail.jp
CR3 and Dectin-1 Collaborate in Macrophage Cytokine Response through Association on Lipid Rafts and Activation of Syk-JNK-AP-1 Pathway
Copyright: © 2015 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Acknowledgments We are grateful to the Second Core Laboratory of Research Core Facility at the National Taiwan University Hospital for confocal microscopy service and providing ultracentrifuge. We thank Dr. William E. Goldman (University of North Carolina, Chapel Hill, NC) for kindly providing WT and ags1-null mutant of H. capsulatum G186A. Funding: This work is supported by research grants 101-2320-B-002-030-MY3 from the Ministry of Science and Technology (http://www.most.gov.tw) and AS-101-TP-B06-3 from Academia Sinica (http://www.sinica.edu.tw) to BAWH. GDB is funded by research grant 102705 from Welcome Trust (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD
A novel auxiliary subunit critical to BK channel function in caenorhabditis elegans
The BK channel is a Ca(2+)- and voltage-gated potassium channel with many important physiological functions. To identify proteins important to its function in vivo, we screened for C. elegans mutants that suppressed a lethargic phenotype caused by expressing a gain-of-function (gf) isoform of the BK channel α-subunit SLO-1. BKIP-1, a small peptide with no significant homology to any previously characterized molecules was thus identified. BKIP-1 and SLO-1 showed similar expression and subcellular localization patterns, and appeared to interact physically through discrete domains. bkip-1 loss-of-function (lf) mutants phenocopied slo-1(lf) mutants in behavior and synaptic transmission, and suppressed the lethargy, egg-laying defect, and deficient neurotransmitter release caused by SLO-1(gf). In heterologous expression systems, BKIP-1 decreased the activation rate and shifted the conductance-voltage (G-V) relationship of SLO-1 in a Ca(2+)-dependent manner, and increased SLO-1 surface expression. Thus, BKIP-1 is a novel auxiliary subunit critical to SLO-1 function in vivo
Cancer stem cells, not bulk tumor cells, determine mechanisms of resistance to SMO inhibitors.
The emergence of treatment resistance significantly reduces the clinical utility of many effective targeted therapies. Although both genetic and epigenetic mechanisms of drug resistance have been reported, whether these mechanisms are stochastically selected in individual tumors or governed by a predictable underlying principle is unknown. Here, we report that the dependence of cancer stem cells (CSCs), not bulk tumor cells, on the targeted pathway determines the molecular mechanism of resistance in individual tumors. Using both spontaneous and transplantable mouse models of sonic hedgehog (SHH) medulloblastoma (MB) treated with an SHH/Smoothened inhibitor, sonidegib/LDE225, we show that genetic-based resistance occurs only in tumors that contain SHH-dependent CSCs (SD-CSCs). In contrast, SHH MBs containing SHH-dependent bulk tumor cells but SHH-independent CSCs (SI-CSCs) acquire resistance through epigenetic reprogramming. Mechanistically, elevated proteasome activity in SMOi-resistant SI-CSC MBs alters the tumor cell maturation trajectory through enhanced degradation of specific epigenetic regulators, including histone acetylation machinery components, resulting in global reductions in H3K9Ac, H3K14Ac, H3K56Ac, H4K5Ac, and H4K8Ac marks and gene expression changes. These results provide new insights into how selective pressure on distinct tumor cell populations contributes to different mechanisms of resistance to targeted therapies. This insight provides a new conceptual framework to understand responses and resistance to SMOis and other targeted therapies
Whole Genome Distribution and Ethnic Differentiation of Copy Number Variation in Caucasian and Asian Populations
Although copy number variation (CNV) has recently received much attention as a form of structure variation within the human genome, knowledge is still inadequate on fundamental CNV characteristics such as occurrence rate, genomic distribution and ethnic differentiation. In the present study, we used the Affymetrix GeneChip® Mapping 500K Array to discover and characterize CNVs in the human genome and to study ethnic differences of CNVs between Caucasians and Asians. Three thousand and nineteen CNVs, including 2381 CNVs in autosomes and 638 CNVs in X chromosome, from 985 Caucasian and 692 Asian individuals were identified, with a mean length of 296 kb. Among these CNVs, 190 had frequencies greater than 1% in at least one ethnic group, and 109 showed significant ethnic differences in frequencies (p<0.01). After merging overlapping CNVs, 1135 copy number variation regions (CNVRs), covering approximately 439 Mb (14.3%) of the human genome, were obtained. Our findings of ethnic differentiation of CNVs, along with the newly constructed CNV genomic map, extend our knowledge on the structural variation in the human genome and may furnish a basis for understanding the genomic differentiation of complex traits across ethnic groups
Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target.
A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer
Comparison of heavy-ion transport simulations: Collision integral with pions and Δ resonances in a box
We compare ten transport codes for a system confined in a box, aiming at
improved handling of the production of resonances and pions, which is
indispensable for constraining high-density symmetry energy from observables
such as the yield ratio in heavy-ion collisions. The system in a
box is initialized with nucleons at saturation density and at 60 MeV
temperature. The reactions and
are implemented, but the Pauli blocking and the
mean-field potential are deactivated in the present comparison. Results are
compared to those from the two reference cases of a chemically equilibrated
ideal gas mixture and of the rate equation. In the results of the numbers of
and , deviations from the reference values are observed in many
codes, and they depend significantly on the size of the time step. These
deviations are tied to different ways in ordering the sequence of collisions
and decays, that take place in the same time step. Better agreements are seen
in the reaction rates and the number ratios among the isospin species of
and . These are, however, affected by the correlations, which are
absent in the Boltzmann equation, but are induced by the way particle
scatterings are treated in transport calculations. The uncertainty in the
transport-code predictions of the ratio for the system
initialized at n/p = 1.5, after letting the existing resonances decay,
is found to be within a few percent, which is sufficiently small so that it
does not strongly impact constraining the high-density symmetry energy from
heavy-ion collisions. Most of the sources of uncertainties have been
understood, and individual codes may be further improved. This investigation
will be extended in the future to heavy-ion collisions to ensure the problems
identified here remain under control.Comment: 36 pages, 27 figures; a new Fig. 21 and revised results from some
codes, achieving improved and consistent understandin
Genome-Wide Association Analyses Identify SPOCK as a Key Novel Gene Underlying Age at Menarche
For females, menarche is a most significant physiological event. Age at menarche (AAM) is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largely unknown. To identify genetic factors underlying AAM variation, a genome-wide association study (GWAS) examining about 380,000 SNPs was conducted in 477 Caucasian women. A follow-up replication study was performed to validate our major GWAS findings using two independent Caucasian cohorts with 854 siblings and 762 unrelated subjects, respectively, and one Chinese cohort of 1,387 unrelated subjects—all females. Our GWAS identified a novel gene, SPOCK (Sparc/Osteonectin, CWCV, and Kazal-like domains proteoglycan), which had seven SNPs associated with AAM with genome-wide false discovery rate (FDR) q<0.05. Six most significant SNPs of the gene were selected for validation in three independent replication cohorts. All of the six SNPs were replicated in at least one cohort. In particular, SNPs rs13357391 and rs1859345 were replicated both within and across different ethnic groups in all three cohorts, with p values of 5.09×10−3 and 4.37×10−3, respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19×10−5 and 1.02×10−4, respectively, in all three replication cohorts. Interestingly, SPOCK can inhibit activation of MMP-2 (matrix metalloproteinase-2), a key factor promoting endometrial menstrual breakdown and onset of menstrual bleeding. Our findings, together with the functional relevance, strongly supported that the SPOCK gene underlies variation of AAM
Expanding LAGLIDADG endonuclease scaffold diversity by rapidly surveying evolutionary sequence space
LAGLIDADG homing endonucleases (LHEs) are a family of highly specific DNA endonucleases capable of recognizing target sequences ∼20 bp in length, thus drawing intense interest for their potential academic, biotechnological and clinical applications. Methods for rational design of LHEs to cleave desired target sites are presently limited by a small number of high-quality native LHEs to serve as scaffolds for protein engineering—many are unsatisfactory for gene targeting applications. One strategy to address such limitations is to identify close homologs of existing LHEs possessing superior biophysical or catalytic properties. To test this concept, we searched public sequence databases to identify putative LHE open reading frames homologous to the LHE I-AniI and used a DNA binding and cleavage assay using yeast surface display to rapidly survey a subset of the predicted proteins. These proteins exhibited a range of capacities for surface expression and also displayed locally altered binding and cleavage specificities with a range of in vivo cleavage activities. Of these enzymes, I-HjeMI demonstrated the greatest activity in vivo and was readily crystallizable, allowing a comparative structural analysis. Taken together, our results suggest that even highly homologous LHEs offer a readily accessible resource of related scaffolds that display diverse biochemical properties for biotechnological applications
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