Article added to library!
x
Pubchase is a service of protocols.io - free, open access, crowdsourced protocols repository. Explore protocols.
Sign in
Reset password
or connect with
Facebook
By signing in you are agreeing to our
Terms Of Service and Privacy Policy
Systems Biology
ING4 suppresses hepatocellular carcinoma via a NF-κB/miR-155/FOXO3a signaling axis.
Feb 14, 2019   International Journal Of Biological Sciences
Qian F, Hu Q, Tian Y, Wu J, Li D, Tao M, Qin L, Shen B, Xie Y
ING4 suppresses hepatocellular carcinoma via a NF-κB/miR-155/FOXO3a signaling axis.
Feb 14, 2019
International Journal Of Biological Sciences
The tumor suppressor ING4 has been shown to be reduced in human HCC. The alteration of ING4 contributes to HCC progression. However, its effect in HCC and the potential mechanism is largely unclear. Herein, we found that downregulation of ING4 in HCC tumor tissues was closely associated with cancer staging, tumor size and vascular invasion. Lentivirus-mediated ING4 overexpression significantly inhibited proliferation, migration and invasion, and induced cell cycle G1 phase arrest and apoptosis in MHCC97H human HCC cells. Moreover, overexpression of ING4 dramatically suppressed MHCC97H tumor cell growth and metastasis to lung in vivo in athymic BALB/c nude mice. Mechanistic studies revealed that overexpression of ING4 markedly increased expression of FOXO3a both at the mRNA and protein level as well as enhanced nuclear level and transcriptional activity of FOXO3a in MHCC97H tumor cells. In addition, ING4 repressed transcriptional activity of NF-κB and expression of miR-155 targeting FOXO3a. Knockdown of ING4 exhibited opposing effects in MHCC97L human HCC cells. Interestingly, knockdown of FOXO3a attenuated not only ING4-elicited tumor suppression but also ING4-mediated regulatory effect on FOXO3a downstream targets, confirming that FOXO3a is involved in ING4-directed tumor-inhibitory effect in HCC. Overexpression of miR-155 attenuated ING4-induced upregulation of FOXO3a, whereas inhibition of miR-155 blunted ING4 knockdown-induced reduction of FOXO3a. Furthermore, inhibition of NF-κB markedly impaired ING4 knockdown-induced upregulation of miR-155 and downregulation of FOXO3a. Taken together, our study provided the first compelling evidence that ING4 can suppress human HCC growth and metastasis to a great extent via a NF-κB/miR-155/FOXO3a pathway.
Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy.
Feb 12, 2019   Cancer Cell
Gide TN, Quek C, Menzies AM, Tasker AT, Shang P,   . . . . . .   , Silva IPD, Batten M, Scolyer RA, Long GV, Wilmott JS
Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy.
Feb 12, 2019
Cancer Cell
Cancer immunotherapies provide survival benefits in responding patients, but many patients fail to respond. Identifying the biology of treatment response and resistance are a priority to optimize drug selection and improve patient outcomes. We performed transcriptomic and immune profiling on 158 tumor biopsies from melanoma patients treated with anti-PD-1 monotherapy (n = 63) or combined anti-PD-1 and anti-CTLA-4 (n = 57). These data identified activated T cell signatures and T cell populations in responders to both treatments. Further mass cytometry analysis identified an EOMES+CD69+CD45RO+ effector memory T cell phenotype that was significantly more abundant in responders to combined immunotherapy compared with non-responders (n = 18). The gene expression profile of this population was associated with longer progression-free survival in patients treated with single agent and greater tumor shrinkage in both treatments.
Genomic annotation of disease-associated variants reveals shared functional contexts.
Feb 13, 2019   Diabetologia
Kyono Y, Kitzman JO, Parker SCJ
Genomic annotation of disease-associated variants reveals shared functional contexts.
Feb 13, 2019
Diabetologia
Variation in non-coding DNA, encompassing gene regulatory regions such as enhancers and promoters, contributes to risk for complex disorders, including type 2 diabetes. While genome-wide association studies have successfully identified hundreds of type 2 diabetes loci throughout the genome, the vast majority of these reside in non-coding DNA, which complicates the process of determining their functional significance and level of priority for further study. Here we review the methods used to experimentally annotate these non-coding variants, to nominate causal variants and to link them to diabetes pathophysiology. In recent years, chromatin profiling, massively parallel sequencing, high-throughput reporter assays and CRISPR gene editing technologies have rapidly become indispensable tools. Rather than treating individual variants in isolation, we discuss the importance of accounting for context, both genetic (such as flanking DNA sequence) and environmental (such as cellular state or environmental exposure). Incorporating these features shows promise in terms of revealing biologically convergent molecular signatures across distant and seemingly unrelated loci. Studying regulatory elements in the proper context will be crucial for interpreting the functional significance of disease-associated variants and applying the resulting knowledge to improve patient care.
Niraparib activates interferon signaling and potentiates anti-PD-1 antibody efficacy in tumor models.
Feb 13, 2019   Scientific Reports
Wang Z, Sun K, Xiao Y, Feng B, Mikule K, Ma X, Feng N, Vellano CP, Federico L, Marszalek JR, Mills GB, Hanke J, Ramaswamy S, Wang J
Niraparib activates interferon signaling and potentiates anti-PD-1 antibody efficacy in tumor models.
Feb 13, 2019
Scientific Reports
PARP inhibitors have been proven clinically efficacious in platinum-responsive ovarian cancer regardless of BRCA1/2 status and in breast cancers with germline BRCA1/2 mutation. However, resistance to PARP inhibitors may preexist or evolve during treatment in many cancer types and may be overcome by combining PARP inhibitors with other therapies, such as immune checkpoint inhibitors, which confer durable responses and are rapidly becoming the standard of care for multiple tumor types. This study investigated the therapeutic potential of combining niraparib, a highly selective PARP1/2 inhibitor, with anti-PD-1 immune checkpoint inhibitors in preclinical tumor models. Our results indicate that niraparib treatment increases the activity of the type I (alpha) and type II (gamma) interferon pathways and enhances the infiltration of CD8+ cells and CD4+ cells in tumors. When coadministered in immunocompetent models, the combination of niraparib and anti-PD-1 demonstrated synergistic antitumor activities in both BRCA-proficient and BRCA-deficient tumors. Interestingly, mice with tumors cured by niraparib monotherapy completely rejected tumor growth upon rechallenge with the same tumor cell line, suggesting the potential establishment of immune memory in animals treated with niraparib monotherapy. Taken together, our findings uncovered immunomodulatory effects of niraparib that may sensitize tumors to immune checkpoint blockade therapies.
On-target and off-target effects of novel orthosteric and allosteric activators of GPR84.
Feb 13, 2019   Scientific Reports
Mancini SJ, Mahmud ZA, Jenkins L, Bolognini D, Newman R, Barnes M, Edye ME, McMahon SB, Tobin AB, Milligan G
On-target and off-target effects of novel orthosteric and allosteric activators of GPR84.
Feb 13, 2019
Scientific Reports
Many members of the G protein-coupled receptor family, including examples with clear therapeutic potential, remain poorly characterised. This often reflects limited availability of suitable tool ligands with which to interrogate receptor function. In the case of GPR84, currently a target for the treatment of idiopathic pulmonary fibrosis, recent times have seen the description of novel orthosteric and allosteric agonists. Using 2-(hexylthiol)pyrimidine-4,6 diol (2-HTP) and di(5,7-difluoro-1H-indole-3-yl)methane (PSB-16671) as exemplars of each class, in cell lines transfected to express either human or mouse GPR84, both ligands acted as effective on-target activators and with high co-operativity in their interactions. This was also the case in lipopolysaccharide-activated model human and mouse immune cell lines. However in mouse bone-marrow-derived neutrophils, where expression of GPR84 is particularly high, the capacity of PSB-16671 but not of 2-HTP to promote G protein activation was predominantly off-target because it was not blocked by an antagonist of GPR84 and was preserved in neutrophils isolated from GPR84 deficient mice. These results illustrate the challenges of attempting to study and define functions of poorly characterised receptors using ligands that have been developed via medicinal chemistry programmes, but where assessed activity has been limited largely to the initially identified target.
Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer.
Feb 16, 2019   Nature Communications
Li X, Mak VCY, Zhou Y, Wang C, Wong ESY, Sharma R, Lu Y, Cheung ANY, Mills GB, Cheung LWT
Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer.
Feb 16, 2019
Nature Communications
Copy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.
Crystal structure of MICU2 and comparison with MICU1 reveal insights into the uniporter gating mechanism.
Feb 13, 2019   Proceedings Of The National Academy Of Sciences Of The United States Of America
Kamer KJ, Jiang W, Kaushik VK, Mootha VK, Grabarek Z
Crystal structure of MICU2 and comparison with MICU1 reveal insights into the uniporter gating mechanism.
Feb 13, 2019
Proceedings Of The National Academy Of Sciences Of The United States Of America
The mitochondrial uniporter is a Ca2+-channel complex resident within the organelle's inner membrane. In mammalian cells the uniporter's activity is regulated by Ca2+ due to concerted action of MICU1 and MICU2, two paralogous, but functionally distinct, EF-hand Ca2+-binding proteins. Here we present the X-ray structure of the apo form of Mus musculus MICU2 at 2.5-Å resolution. The core structure of MICU2 is very similar to that of MICU1. It consists of two lobes, each containing one canonical Ca2+-binding EF-hand (EF1, EF4) and one structural EF-hand (EF2, EF3). Two molecules of MICU2 form a symmetrical dimer stabilized by highly conserved hydrophobic contacts between exposed residues of EF1 of one monomer and EF3 of another. Similar interactions stabilize MICU1 dimers, allowing exchange between homo- and heterodimers. The tight EF1-EF3 interface likely accounts for the structural and functional coupling between the Ca2+-binding sites in MICU1, MICU2, and their complex that leads to the previously reported Ca2+-binding cooperativity and dominant negative effect of mutation of the Ca2+-binding sites in either protein. The N- and C-terminal segments of the two proteins are distinctly different. In MICU2 the C-terminal helix is significantly longer than in MICU1, and it adopts a more rigid structure. MICU2's C-terminal helix is dispensable in vitro for its interaction with MICU1 but required for MICU2's function in cells. We propose that in the MICU1-MICU2 oligomeric complex the C-terminal helices of both proteins form a central semiautonomous assembly which contributes to the gating mechanism of the uniporter.
Epigenomic analysis reveals DNA motifs regulating histone modifications in human and mouse.
Feb 16, 2019   Proceedings Of The National Academy Of Sciences Of The United States Of America
Ngo V, Chen Z, Zhang K, Whitaker JW, Wang M, Wang W
Epigenomic analysis reveals DNA motifs regulating histone modifications in human and mouse.
Feb 16, 2019
Proceedings Of The National Academy Of Sciences Of The United States Of America
Histones are modified by enzymes that act in a locus, cell-type, and developmental stage-specific manner. The recruitment of enzymes to chromatin is regulated at multiple levels, including interaction with sequence-specific DNA-binding factors. However, the DNA-binding specificity of the regulatory factors that orchestrate specific histone modifications has not been broadly mapped. We have analyzed 6 histone marks (H3K4me1, H3K4me3, H3K27ac, H3K27me3, K3H9me3, H3K36me3) across 121 human cell types and tissues from the NIH Roadmap Epigenomics Project as well as 8 histone marks (with addition of H3K4me2 and H3K9ac) from the mouse ENCODE Consortium. We have identified 361 and 369 DNA motifs in human and mouse, respectively, that are the most predictive of each histone mark. Interestingly, 107 human motifs are conserved between the two species. In human embryonic cell line H1, we mutated only the found DNA motifs at particular loci and the significant reduction of H3K27ac levels validated the regulatory roles of the perturbed motifs. The functionality of these motifs was also supported by the evidence that histone-associated motifs, especially H3K4me3 motifs, significantly overlap with the expression of quantitative trait loci SNPs in cancer patients more than the known and random motifs. Furthermore, we observed possible feedbacks to control chromatin dynamics as the found motifs appear in the promoters or enhancers associated with various histone modification enzymes. These results pave the way toward revealing the molecular mechanisms of epigenetic events, such as histone modification dynamics and epigenetic priming.
Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling.
Feb 13, 2019   MBio
Bossler F, Kuhn BJ, Günther T, Kraemer SJ, Khalkar P,   . . . . . .   , Rösl F, Grundhoff A, Krijgsveld J, Hoppe-Seyler K, Hoppe-Seyler F
Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling.
Feb 13, 2019
MBio
Hypoxia is linked to therapeutic resistance and poor clinical prognosis for many tumor entities, including human papillomavirus (HPV)-positive cancers. Notably, HPV-positive cancer cells can induce a dormant state under hypoxia, characterized by a reversible growth arrest and strong repression of viral E6/E7 oncogene expression, which could contribute to therapy resistance, immune evasion and tumor recurrence. The present work aimed to gain mechanistic insights into the pathway(s) underlying HPV oncogene repression under hypoxia. We show that E6/E7 downregulation is mediated by hypoxia-induced stimulation of AKT signaling. Ablating AKT function in hypoxic HPV-positive cancer cells by using chemical inhibitors efficiently counteracts E6/E7 repression. Isoform-specific activation or downregulation of AKT1 and AKT2 reveals that both AKT isoforms contribute to hypoxic E6/E7 repression and act in a functionally redundant manner. Hypoxic AKT activation and consecutive E6/E7 repression is dependent on the activities of the canonical upstream AKT regulators phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR) complex 2 (mTORC2). Hypoxic downregulation of E6/E7 occurs, at least in part, at the transcriptional level. Modulation of E6/E7 expression by the PI3K/mTORC2/AKT cascade is hypoxia specific and not observed in normoxic HPV-positive cancer cells. Quantitative proteome analyses identify additional factors as candidates to be involved in hypoxia-induced activation of the PI3K/mTORC2/AKT signaling cascade and in the AKT-dependent repression of the E6/E7 oncogenes under hypoxia. Collectively, these data uncover a functional key role of the PI3K/mTORC2/AKT signaling cascade for viral oncogene repression in hypoxic HPV-positive cancer cells and provide new insights into the poorly understood cross talk between oncogenic HPVs and their host cells under hypoxia.IMPORTANCE Oncogenic HPV types are major human carcinogens. Under hypoxia, HPV-positive cancer cells can repress the viral E6/E7 oncogenes and induce a reversible growth arrest. This response could contribute to therapy resistance, immune evasion, and tumor recurrence upon reoxygenation. Here, we uncover evidence that HPV oncogene repression is mediated by hypoxia-induced activation of canonical PI3K/mTORC2/AKT signaling. AKT-dependent downregulation of E6/E7 is only observed under hypoxia and occurs, at least in part, at the transcriptional level. Quantitative proteome analyses identify additional factors as candidates to be involved in AKT-dependent E6/E7 repression and/or hypoxic PI3K/mTORC2/AKT activation. These results connect PI3K/mTORC2/AKT signaling with HPV oncogene regulation, providing new mechanistic insights into the cross talk between oncogenic HPVs and their host cells.
Long-Term Transcriptional Activity at Zero Growth of a Cosmopolitan Rare Biosphere Member.
Feb 13, 2019   MBio
Hausmann B, Pelikan C, Rattei T, Loy A, Pester M
Long-Term Transcriptional Activity at Zero Growth of a Cosmopolitan Rare Biosphere Member.
Feb 13, 2019
MBio
Microbial diversity in the environment is mainly concealed within the rare biosphere (all species with
MaxQuant.Live enables global targeting of more than 25,000 peptides.
Feb 13, 2019   Molecular & Cellular Proteomics : MCP
Wichmann C, Meier F, Virreira Winter S, Brunner AD, Cox J, Mann M
MaxQuant.Live enables global targeting of more than 25,000 peptides.
Feb 13, 2019
Molecular & Cellular Proteomics : MCP
Mass spectrometry (MS)-based proteomics is often performed in a shotgun format, in which as many peptide precursors as possible are selected from full or MS1 scans so that their fragment spectra can be recorded in MS2 scans. While achieving great proteome depths, shotgun proteomics cannot guarantee that each precursor will be fragmented in each run. In contrast, targeted proteomics aims to reproducibly and sensitively record a restricted number of precursor/fragment combinations in each run, based on pre-scheduled mass-to-charge and retention time windows. Here we set out to unify these two concepts by a global targeting approach in which an arbitrary number of precursors of interest are detected in real-time, followed by standard fragmentation or advanced peptide-specific analyses. We made use of a fast application programming interface to a quadrupole Orbitrap instrument and real-time recalibration in mass, retention time and intensity dimensions to predict precursor identity. MaxQuant.Live is freely available (www.maxquant.live) and has a graphical user interface to specify many pre-defined data acquisition strategies. Acquisition speed is as fast as with the vendor software and the power of our approach is demonstrated with the acquisition of breakdown curves for hundreds of precursors of interest. We also uncover precursors that are not even visible in MS1 scans, using elution time prediction based on the auto-adjusted retention time alone. Finally, we successfully recognized and targeted more than 25,000 peptides in single LC-MS runs. Global targeting combines the advantages of two classical approaches in MS-based proteomics, while greatly expanding the analytical toolbox.
Analysis of the molecular basis of fruit cracking susceptibility in Litchi chinensis cv. Baitangying by transcriptome and quantitative proteome profiling.
Feb 14, 2019   Journal Of Plant Physiology
Wang J, Gao X, Ma Z, Chen J, Liu Y
Analysis of the molecular basis of fruit cracking susceptibility in Litchi chinensis cv. Baitangying by transcriptome and quantitative proteome profiling.
Feb 14, 2019
Journal Of Plant Physiology
Fruit cracking is a serious problem in Litchi chinensis cv. Baitangying orchards, but few advances have been made in understanding the molecular basis of cracking susceptibility in 'Baitangying'. In this work, we conducted transcriptome and quantitative proteome analyses of the pericarps of three kinds of litchi: noncracking 'Feizixiao' (cracking-resistant cultivar, F), noncracking 'Baitangying' (B), and cracking 'Baitangying' (CB). A total of 101 genes and 14 proteins with the same regulatory changes were found to overlap between CB vs. B and B vs. F, and we focused on these results to avoid the effects of passive progression after fruit cracking. The obtained data suggest that fruit cracking susceptibility in 'Baitangying' is related to pericarp photosynthetic characteristics and the oxidation of unsaturated fatty acids in this cultivar, which lead to changes in cuticle structure. Furthermore, differences in the pericarp hormone balance between 'Baitangying' and 'Feizixiao' may influence the susceptibility of 'Baitangying' to fruit cracking. This integrated analysis of transcriptomic and proteomic data indicates that susceptibility to fruit cracking in 'Baitangying' litchi is regulated both translationally and posttranslationally. Our results may help provide a new perspective for further study of the mechanisms that govern fruit cracking susceptibility in 'Baitangying' litchi and other fruits.
Extracellular peptide Kratos restricts cell death during vascular development and stress in Arabidopsis.
Feb 12, 2019   Journal Of Experimental Botany
Escamez S, Stael S, Vainonen J, Willems P, Jin H, Kimura S, Van Breusegem F, Gevaert K, Wrzaczek M, Tuominen H
Extracellular peptide Kratos restricts cell death during vascular development and stress in Arabidopsis.
Feb 12, 2019
Journal Of Experimental Botany
During plant vascular development, xylem tracheary elements (TEs) form water-conducting, empty pipes through genetically regulated cell death. Cell death is prevented from spreading to non-TEs by unidentified intercellular mechanisms, downstream of METACASPASE9 (MC9)-mediated regulation of autophagy in TEs. Here, we identified differentially abundant extracellular peptides in vascular-differentiating wild type and MC9-downregulated Arabidopsis cell suspensions. The peptide Kratos rescued the abnormally high ectopic non-TE death resulting from either MC9 knockout or TE-specific overexpression of the ATG5 autophagy protein during experimentally induced vascular differentiation in Arabidopsis cotyledons. Kratos also reduced cell death following mechanical damage and extracellular ROS production in Arabidopsis leaves. Stress-induced but not vascular non-TE cell death was enhanced by another identified peptide, Bia. Bia is therefore reminiscent of several known plant cell death-inducing peptides acting as damage-associated molecular patterns. In contrast, Kratos plays a novel extracellular cell survival role in the context of development and during stress response.
Erratum to rhinovirus is associated with severe adult community-acquired pneumonia in China.
Feb 14, 2019   Journal Of Thoracic Disease
Wang K, Xi W, Yang D, Zheng Y, Zhang Y,   . . . . . .   , Hu K, Cao J, Ren L, Huang F, Gao Z
Transcriptional regulation of the genes involved in protein metabolism and processing in Saccharomyces cerevisiae.
Feb 12, 2019   FEMS Yeast Research
Dikicioglu D, Nightingale DJH, Wood V, Lilley KS, Oliver SG
Transcriptional regulation of the genes involved in protein metabolism and processing in Saccharomyces cerevisiae.
Feb 12, 2019
FEMS Yeast Research
Topological analysis of large networks, which focus on a specific biological process or on related biological processes, where functional coherence exists among the interacting members, may provide a wealth of insight into cellular functionality. This work presents an unbiased systems approach to analyze genetic, transcriptional regulatory, and physical interaction networks of yeast genes possessing such functional coherence to gain novel biological insight. The present analysis identified only a few transcriptional regulators amongst a large gene cohort associated with the protein metabolism and processing in yeast. These transcription factors are not functionally required for the maintenance of these tasks in growing cells. Rather, they are involved in rewiring gene transcription in response to such major challenges as starvation, hypoxia, DNA damage, heat shock, or the accumulation of unfolded proteins. Indeed, only a subset of these proteins were captured empirically in the nuclear-enriched fraction of non-stressed yeast cells, suggesting that the transcriptional regulation of protein metabolism and processing in yeast is primarily concerned with maintaining cellular robustness in the face of threat by either internal or external stressors.
Modeling cell proliferation in human acute myeloid leukemia xenografts.
Feb 12, 2019   Bioinformatics (Oxford, England)
Nobile MS, Vlachou T, Spolaor S, Bossi D, Cazzaniga P, Lanfrancone L, Mauri G, Pelicci PG, Besozzi D
Modeling cell proliferation in human acute myeloid leukemia xenografts.
Feb 12, 2019
Bioinformatics (Oxford, England)
Motivation: Acute myeloid leukemia is one of the most common hematological malignancies, characterized by high relapse and mortality rates. The inherent intra-tumor heterogeneity in acute myeloid leukemia is thought to play an important role in disease recurrence and resistance to chemotherapy. Although experimental protocols for cell proliferation studies are well established and widespread, they are not easily applicable to in vivo contexts, and the analysis of related time-series data is often complex to achieve. To overcome these limitations, model-driven approaches can be exploited to investigate different aspects of cell population dynamics. Results: In this work we present ProCell, a novel modeling and simulation framework to investigate cell proliferation dynamics that, differently from other approaches, takes into account the inherent stochasticity of cell division events. We apply ProCell to compare different models of cell proliferation in acute myeloid leukemia, notably leveraging experimental data derived from human xenografts in mice. ProCell is coupled with Fuzzy Self-Tuning Particle Swarm Optimization, a swarm-intelligence settings-free algorithm used to automatically infer the models' parameterizations. Our results provide new insights on the intricate organization of acute myeloid leukemia cells with highly heterogeneous proliferative potential, highlighting the important role played by quiescent cells and proliferating cells characterized by different rates of division in the progression and evolution of the disease, thus hinting at the necessity to further characterize tumor cell subpopulations. Availability: The source code of ProCell and the experimental data used in this work are available under the GPL 2.0 license on GITHUB at the following URL: https://github.com/aresio/ProCell. Supplementary information: Supplementary data are available at Bioinformatics online.
Variational Infinite Heterogeneous Mixture Model for Semi-supervised Clustering of Heart Enhancers.
Feb 12, 2019   Bioinformatics (Oxford, England)
Mehdi TF, Singh G, Mitchell JA, Moses AM
Variational Infinite Heterogeneous Mixture Model for Semi-supervised Clustering of Heart Enhancers.
Feb 12, 2019
Bioinformatics (Oxford, England)
Motivation: Mammalian genomes can contain thousands of enhancers but only a subset are actively driving gene expression in a given cellular context. Integrated genomic datasets can be harnessed to predict active enhancers. One challenge in integration of large genomic datasets is the increasing heterogeneity: continuous, binary and discrete features may all be relevant. Coupled with the typically small numbers of training examples, semi-supervised approaches for heterogeneous data are needed; however, current enhancer prediction methods are not designed to handle heterogeneous data in the semi-supervised paradigm. Results: We implemented a Dirichlet Process Heterogeneous Mixture model that infers Gaussian, Bernoulli and Poisson distributions over features. We derived a novel variational inference algorithm to handle semi-supervised learning tasks where certain observations are forced to cluster together. We applied this model to enhancer candidates in mouse heart tissues based on heterogeneous features. We constrained a small number of known active enhancers to appear in the same cluster, and 47 additional regions clustered with them. Many of these are located near heart-specific genes. The model also predicted 1176 active promoters, suggesting that it can discover new enhancers and promoters. Availability: We created the 'dphmix' Python package: https://pypi.org/project/dphmix/. Supplementary information: Supplementary data are available at Bioinformatics online.
Multifaceted activity of cytokinin in leaf development shapes its size and structure in Arabidopsis.
Feb 12, 2019   The Plant Journal : For Cell And Molecular Biology
Skalák J, Vercruyssen L, Claeys H, Hradilová J, Černý M,   . . . . . .   , Dhondt S, Koukalová Š, Zouhar J, Inzé D, Brzobohatý B
Multifaceted activity of cytokinin in leaf development shapes its size and structure in Arabidopsis.
Feb 12, 2019
The Plant Journal : For Cell And Molecular Biology
Phytohormone cytokinin has been shown to affect many aspects of plant development ranging from the regulation of the shoot apical meristem to leaf senescence. However some studies reported contradictory effects of cytokinin on leaf physiology. Thus, cytokinin treatments cause both chlorosis and increased greening, and both decrease and increase in cell size. To elucidate this multifaceted role of cytokinin in leaf development, we have employed a system of temporal control over the cytokinin pool and investigated the consequences of modulated cytokinin levels in the third leaf of Arabidopsis. We show that at the cell proliferation phase, cytokinin is needed to maintain cell proliferation by blocking the transition to cell expansion and the onset of photosynthesis. Transcriptome profiling revealed regulation by cytokinin of a gene suit previously shown to affect cell proliferation and expansion, and thereby a molecular mechanism by which cytokinin modulates a molecular network underlying the cellular responses. During the cell expansion phase, cytokinin stimulates cell expansion and differentiation. Consequently, a cytokinin excess at the cell expansion phase results in an increased leaf and rosette size fueled by higher cell expansion rate, yielding higher shoot biomass. Proteome profiling revealed the stimulation of primary metabolism by cytokinin, in line with an increased sugar content that is expected to increase turgor pressure, representing the driving force of cell expansion. Thus, the developmental timing of cytokinin content fluctuations, together with a tight control of primary metabolism, is a key factor mediating transitions from cell proliferation to cell expansion in leaves. This article is protected by copyright. All rights reserved.
Generation of a zebrafish SWATH-MS spectral library to quantify 10,000 proteins.
Feb 14, 2019   Scientific Data
Blattmann P, Stutz V, Lizzo G, Richard J, Gut P, Aebersold R
Generation of a zebrafish SWATH-MS spectral library to quantify 10,000 proteins.
Feb 14, 2019
Scientific Data
Sequential window acquisition of all theoretical mass spectra (SWATH-MS) requires a spectral library to extract quantitative measurements from the mass spectrometry data acquired in data-independent acquisition mode (DIA). Large combined spectral libraries containing SWATH assays have been generated for humans and several other organisms, but so far no publicly available library exists for measuring the proteome of zebrafish, a rapidly emerging model system in biomedical research. Here, we present a large zebrafish SWATH spectral library to measure the abundance of 104,185 proteotypic peptides from 10,405 proteins. The library includes proteins expressed in 9 different zebrafish tissues (brain, eye, heart, intestine, liver, muscle, ovary, spleen, and testis) and provides an important new resource to quantify 40% of the protein-coding zebrafish genes. We employ this resource to quantify the proteome across brain, muscle, and liver and characterize divergent expression levels of paralogous proteins in different tissues. Data are available via ProteomeXchange (PXD010876, PXD010869) and SWATHAtlas (PASS01237).
How significant are the public dimensions of faculty work in review, promotion, and tenure documents?
Feb 12, 2019   ELife
Alperin JP, Muñoz Nieves C, Schimanski L, Fischman GE, Niles MT, McKiernan EC
How significant are the public dimensions of faculty work in review, promotion, and tenure documents?
Feb 12, 2019
ELife
Much of the work done by faculty at both public and private universities has significant public dimensions: it is often paid for by public funds; it is often aimed at serving the public good; and it is often subject to public evaluation. To understand how the public dimensions of faculty work are valued, we analyzed review, promotion, and tenure documents from a representative sample of 129 universities in the US and Canada. Terms and concepts related to public and community are mentioned in a large portion of documents, but mostly in ways that relate to service, which is an undervalued aspect of academic careers. Moreover, the documents make significant mention of traditional research outputs and citation-based metrics: however, such outputs and metrics reward faculty work targeted to academics, and often disregard the public dimensions. Institutions that seek to embody their public mission could therefore work towards changing how faculty work is assessed and incentivized.
Monitoring Phenotypic Switching in Candida albicans and the Use of Next-Gen Fluorescence Reporters.
Feb 12, 2019   Current Protocols In Microbiology
Frazer C, Hernday AD, Bennett RJ
Monitoring Phenotypic Switching in Candida albicans and the Use of Next-Gen Fluorescence Reporters.
Feb 12, 2019
Current Protocols In Microbiology
Candida albicans is an opportunistic human fungal pathogen that is able to cause both mucosal and systemic infections. It is also a frequent human commensal, where it is typically found inhabiting multiple niches including the gastrointestinal tract. One of the most remarkable features of C. albicans biology is its ability to undergo heritable and reversible switching between different phenotypic states, a phenomenon known as phenotypic switching. This is best exemplified by the white-opaque switch, in which cells undergo epigenetic transitions between two alternative cellular states. Here, we describe assays to quantify the frequency of switching between states, as well as methods to help identify cells in different phenotypic states. We also describe the use of environmental cues that can induce switching into either the white or opaque state. Finally, we introduce the use of mNeonGreen and mScarlet fluorescent proteins that have been optimized for use in C. albicans and which outperform commonly used fluorescent proteins for both fluorescence microscopy and flow cytometry. © 2019 by John Wiley & Sons, Inc.
Extensive transmission of microbes along the gastrointestinal tract.
Feb 12, 2019   ELife
Schmidt TSB, Hayward MR, Coelho LP, Li SS, Costea PI,   . . . . . .   , Heintz-Buschart A, Sunagawa S, Zeller G, Wilmes P, Bork P
Extensive transmission of microbes along the gastrointestinal tract.
Feb 12, 2019
ELife
The gastrointestinal tract is abundantly colonized by microbes, yet the translocation of oral species to the intestine is considered a rare aberrant event, and a hallmark of disease. By studying salivary and fecal microbial strain populations of 310 species in 470 individuals from five countries, we found that transmission to, and subsequent colonization of, the large intestine by oral microbes is common and extensive among healthy individuals. We found evidence for a vast majority of oral species to be transferable, with increased levels of transmission in colorectal cancer and rheumatoid arthritis patients and, more generally, for species described as opportunistic pathogens. This establishes the oral cavity as an endogenous reservoir for gut microbial strains, and oral-fecal transmission as an important process that shapes the gastrointestinal microbiome in health and disease.
Draft Genome Assembly of the False Spider Mite Brevipalpus yothersi.
Feb 14, 2019   Microbiology Resource Announcements
Navia D, Novelli VM, Rombauts S, Freitas-Astúa J, Santos de Mendonça R,   . . . . . .   , Grbić M, Wybouw N, Breeuwer JAJ, Van Leeuwen T, Van de Peer Y
Draft Genome Assembly of the False Spider Mite Brevipalpus yothersi.
Feb 14, 2019
Microbiology Resource Announcements
The false spider mite Brevipalpus yothersi infests a broad host plant range and has become one of the most economically important species within the genus Brevipalpus. This phytophagous mite inflicts damage by both feeding on plants and transmitting plant viruses. Here, we report the first draft genome sequence of the false spider mite, which is also the first plant virus mite vector to be sequenced. The ∼72 Mb genome (sequenced at 42× coverage) encodes ∼16,000 predicted protein-coding genes.
Oxidative Pathways of Deoxyribose and Deoxyribonate Catabolism.
Feb 16, 2019   MSystems
Price MN, Ray J, Iavarone AT, Carlson HK, Ryan EM, Malmstrom RR, Arkin AP, Deutschbauer AM
Oxidative Pathways of Deoxyribose and Deoxyribonate Catabolism.
Feb 16, 2019
MSystems
Using genome-wide mutant fitness assays in diverse bacteria, we identified novel oxidative pathways for the catabolism of 2-deoxy-d-ribose and 2-deoxy-d-ribonate. We propose that deoxyribose is oxidized to deoxyribonate, oxidized to ketodeoxyribonate, and cleaved to acetyl coenzyme A (acetyl-CoA) and glyceryl-CoA. We have genetic evidence for this pathway in three genera of bacteria, and we confirmed the oxidation of deoxyribose to ketodeoxyribonate in vitro. In Pseudomonas simiae, the expression of enzymes in the pathway is induced by deoxyribose or deoxyribonate, while in Paraburkholderia bryophila and in Burkholderia phytofirmans, the pathway proceeds in parallel with the known deoxyribose 5-phosphate aldolase pathway. We identified another oxidative pathway for the catabolism of deoxyribonate, with acyl-CoA intermediates, in Klebsiella michiganensis. Of these four bacteria, only P. simiae relies entirely on an oxidative pathway to consume deoxyribose. The deoxyribose dehydrogenase of P. simiae is either nonspecific or evolved recently, as this enzyme is very similar to a novel vanillin dehydrogenase from Pseudomonas putida that we identified. So, we propose that these oxidative pathways evolved primarily to consume deoxyribonate, which is a waste product of metabolism. IMPORTANCE Deoxyribose is one of the building blocks of DNA and is released when cells die and their DNA degrades. We identified a bacterium that can grow with deoxyribose as its sole source of carbon even though its genome does not contain any of the known genes for breaking down deoxyribose. By growing many mutants of this bacterium together on deoxyribose and using DNA sequencing to measure the change in the mutants' abundance, we identified multiple protein-coding genes that are required for growth on deoxyribose. Based on the similarity of these proteins to enzymes of known function, we propose a 6-step pathway in which deoxyribose is oxidized and then cleaved. Diverse bacteria use a portion of this pathway to break down a related compound, deoxyribonate, which is a waste product of metabolism. Our study illustrates the utility of large-scale bacterial genetics to identify previously unknown metabolic pathways.
Gene expression variability in human skeletal muscle transcriptome responses to acute resistance exercise.
Feb 13, 2019   Experimental Physiology
Bonafiglia JT, Menzies KJ, Gurd BJ
Gene expression variability in human skeletal muscle transcriptome responses to acute resistance exercise.
Feb 13, 2019
Experimental Physiology
NEW FINDINGS: What is the central question of this study? Does exercise, independent of random error and within-subject variability, contribute to the variability in gene expression responses to an acute bout of resistance exercise? What is the main finding and its importance? A reanalysis of publicly-available microarray data revealed that variability in observed gene expression responses for a subset of genes could be partially attributable to an effect of acute resistance exercise. These finding support the notion that individual responsiveness explains a portion of the variability in observed gene expression responses to acute resistance exercise. ABSTRACT: The purpose of this study was to use publicly available transcriptomic data to determine whether variability in gene expression responses to an acute bout of resistance exercise (AR) can be attributable to an effect AR per se. We examined microarray data from a previous study that collected skeletal muscle biopsies before and 24 hours after AR or a no-exercise time-matched control period (CTL). By subtracting the standard deviation (SD) in the observed responses to CTL from AR, we determined that AR contributed to the variability in the observed gene expression responses for many (∼31,000), but not all, transcripts included on the Affymetrix Human Genome chips. AR had a large effect on variability in the observed gene expression responses in 1,290 genes that was not attributed to any technical/biological variability associated with repeated measurements. Pathway analysis using WebGestalt revealed that several of these 1,290 genes are involved in pathways known to regulate skeletal muscle adaptations to chronic resistance training (CR). These results suggest that variability in the observed gene expression responses for a subset of genes could be partially attributable to an effect of AR. This article is protected by copyright. All rights reserved.

The link you entered does not seem to be valid

Please make sure the link points to nature.com contains a valid shared_access_token

Downloading PDF to your library...

Uploading PDF...

PDF uploading

Delete tag: