PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (107)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
1.  Activation of MrgC receptor inhibits N-type calcium channels in small-diameter primary sensory neurons in mice 
Pain  2014;155(8):1613-1621.
Mas-related G-protein-coupled receptor subtype C (mouse MrgC11 and rat rMrgC), expressed specifically in small-diameter primary sensory neurons, may constitute a novel pain inhibitory mechanism. We have shown previously that intrathecal administration of MrgC-selective agonists can strongly attenuate persistent pain in various animal models. However, the underlying mechanisms for MrgC agonist-induced analgesia remain elusive. Here, we conducted patch-clamp recordings to test the effect of MrgC agonists on high-voltage-activated (HVA) calcium current in small-diameter dorsal root ganglion (DRG) neurons. Using pharmacological approaches, we show for the first time that an MrgC agonist (JHU58) selectively and dose-dependently inhibits N-type, but not L- or P/Q-type, HVA calcium channels in mouse DRG neurons. Activation of HVA calcium channels is important to neurotransmitter release and synaptic transmission. Patch-clamp recordings in spinal cord slices showed that JHU58 attenuated the evoked excitatory postsynaptic currents in substantia gelatinosa (SG) neurons in wild-type mice, but not in Mrg knockout mice, after peripheral nerve injury. These findings indicate that activation of endogenously expressed MrgC receptors at central terminals of primary sensory fibers may decrease peripheral excitatory inputs onto SG neurons. Together, these results suggest potential cellular and molecular mechanisms that may contribute to intrathecal MrgC agonist-induced analgesia. Because MrgC shares substantial genetic homogeneity with human MrgX1, our findings may suggest a rationale for developing intrathecally delivered MrgX1 receptor agonists to treat pathological pain in humans and provide critical insight regarding potential mechanisms that may underlie its analgesic effects.
doi:10.1016/j.pain.2014.05.008
PMCID: PMC4104261  PMID: 24813294
MrgC; calcium channel; dorsal root ganglion; nerve injury; pain
2.  Acupuncture and regulation of gastrointestinal function 
In China, acupuncture has been considered an effective method for treating gastrointestinal (GI) dysfunction diseases for thousands of years. In fact, acupuncture has gained progressive acceptance from both practitioners and patients worldwide. However, the therapeutic effects and underlying mechanisms in treating GI dysfunction have not yet been established due to a lack of systematic and comprehensive review articles. Therefore, the aim of this review is to discuss the efficacy of acupuncture as a treatment for GI dysfunction and the associated underlying mechanisms. A search of PubMed was conducted for articles that were published over the past 10 years using the terms “acupuncture”, “gastrointestine”, and other relevant keywords. In the following review, we describe the effect and underlying mechanisms of acupuncture on GI function from the perspectives of GI motility, visceral sensitivity, the GI barrier, and the brain-gut axis. The dual regulatory effects of acupuncture may manifest by promoting gastric peristalsis in subjects with low initial gastric motility, and suppressing peristalsis in subjects with active initial motility. In addition, the regulation of acupuncture on gastric motility may be intensity-dependent. Our findings suggest that further studies are needed to investigate the effects and more systematic mechanisms in treating GI dysfunction, and to promote the application of acupuncture for the treatment of GI diseases.
doi:10.3748/wjg.v21.i27.8304
PMCID: PMC4507100  PMID: 26217082
Acupuncture; Gastrointestinal motility; Gastrointestinal barrier; Visceral sensitivity; Brain-gut axis
3.  Population dynamics of cancer cells with cell state conversions 
Quantitative biology  2013;1(3):201-208.
Cancer stem cell (CSC) theory suggests a cell-lineage structure in tumor cells in which CSCs are capable of giving rise to the other non-stem cancer cells (NSCCs) but not vice versa. However, an alternative scenario of bidirectional interconversions between CSCs and NSCCs was proposed very recently. Here we present a general population model of cancer cells by integrating conventional cell divisions with direct conversions between different cell states, namely, not only can CSCs differentiate into NSCCs by asymmetric cell division, NSCCs can also dedifferentiate into CSCs by cell state conversion. Our theoretical model is validated when applying the model to recent experimental data. It is also found that the transient increase in CSCs proportion initiated from the purified NSCCs subpopulation cannot be well predicted by the conventional CSC model where the conversion from NSCCs to CSCs is forbidden, implying that the cell state conversion is required especially for the transient dynamics. The theoretical analysis also gives the condition such that our general model can be equivalently reduced into a simple Markov chain with only cell state transitions keeping the same cell proportion dynamics.
doi:10.1007/s40484-013-0014-2
PMCID: PMC4467561  PMID: 26085954
4.  Response of Arbuscular Mycorrhizal Fungi to Hydrologic Gradients in the Rhizosphere of Phragmites australis (Cav.) Trin ex. Steudel Growing in the Sun Island Wetland 
BioMed Research International  2015;2015:810124.
Within the rhizosphere, AM fungi are a sensitive variable to changes of botanic and environmental conditions, and they may interact with the biomass of plant and other microbes. During the vegetative period of the Phragmites australis growing in the Sun Island Wetland (SIW), the variations of AM fungi colonization were studied. Root samples of three hydrologic gradients generally showed AM fungi colonization, suggesting that AM fungi have the ability for adaptation to flooded habitats. There were direct and indirect hydrological related effects with respect to AM fungi biomass, which interacted simultaneously in the rhizosphere. Though water content in soil and reed growth parameters were both positively associated with AM fungi colonization, only the positive correlations between reed biomass parameters and the colonization could be expected, or both the host plant biomass and the AM fungi could be beneficial. The variations in response of host plant to the edaphic and hydrologic conditions may influence the effectiveness of the plant-mycorrhizal association. This study included a hydrologic component to better assess the role and distribution of AM fungi in wetland ecosystems. And because of that, the range of AM fungi was extended, since they actually showed a notable adaptability to hydrologic gradients.
doi:10.1155/2015/810124
PMCID: PMC4469805  PMID: 26146633
5.  NOD1 and NOD2 Genetic Variants in Association with Risk of Gastric Cancer and Its Precursors in a Chinese Population 
PLoS ONE  2015;10(5):e0124949.
Background
Genetic variants of nucleotide-binding oligomerization domain-containing protein (NOD) may influence the outcome of Helicobacter pylori (H. pylori) infection and gastric carcinogenesis. To explore genetic variants of NOD1 and NOD2 in association with gastric cancer (GC) and its precursors, a population-based study was conducted in Linqu County, China.
Methods
TagSNPs of NOD1 and NOD2 were genotyped by Sequenom MASS array in 132 GCs, and 1,198 subjects with precancerous gastric lesions, and were correlated with evolution of gastric lesions in 766 subjects with follow-up data.
Results
Among seven tagSNPs, NOD1 rs2709800 and NOD2 rs718226 were associated with gastric lesions. NOD1 rs2709800 TG genotype carriers had a decreased risk of intestinal metaplasia (IM, OR: 0.53; 95% CI: 0.31–0.92), while NOD2 rs718226 G allele (AG/GG) showed increased risks of dysplasia (DYS, OR: 2.96; 95% CI: 1.86–4.71) and GC (OR: 2.35; 95% CI: 1.24–4.46). Moreover, an additive interaction between rs718226 and H. pylori was found in DYS or GC with synergy index of 3.08 (95% CI: 1.38–6.87) or 3.99 (95% CI: 1.55–10.22), respectively. The follow-up data indicated that NOD2 rs2111235 C allele (OR: 0.52; 95% CI: 0.32–0.83) and rs7205423 G allele (OR: 0.56; 95% CI: 0.35–0.89) were associated with decreased risk of progression in H. pylori-infected subjects.
Conclusions
NOD1 rs2709800, NOD2 rs718226, rs2111235, rs7205423 and interaction between rs718226 and H. pylori infection may be related to risk of gastric lesions.
doi:10.1371/journal.pone.0124949
PMCID: PMC4416772  PMID: 25933107
6.  Identification and analysis of unitary loss of long-established protein-coding genes in Poaceae shows evidences for biased gene loss and putatively functional transcription of relics 
Background
Long-established protein-coding genes may lose their coding potential during evolution (“unitary gene loss”). Members of the Poaceae family are a major food source and represent an ideal model clade for plant evolution research. However, the global pattern of unitary gene loss in Poaceae genomes as well as the evolutionary fate of lost genes are still less-investigated and remain largely elusive.
Results
Using a locally developed pipeline, we identified 129 unitary gene loss events for long-established protein-coding genes from four representative species of Poaceae, i.e. brachypodium, rice, sorghum and maize. Functional annotation suggested that the lost genes in all or most of Poaceae species are enriched for genes involved in development and response to endogenous stimulus. We also found that 44 mutated genomic loci of lost genes, which we referred as relics, were still actively transcribed, and of which 84% (37 of 44) showed significantly differential expression across different tissues. More interestingly, we found that there were totally five expressed relics may function as competitive endogenous RNA in brachypodium, rice and sorghum genome.
Conclusions
Based on comparative genomics and transcriptome data, we firstly compiled a comprehensive catalogue of unitary gene loss events in Poaceae species and characterized a statistically significant functional preference for these lost genes as well showed the potential of relics functioning as competitive endogenous RNAs in Poaceae genomes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12862-015-0345-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12862-015-0345-x
PMCID: PMC4425925  PMID: 25927997
Unitary gene loss; Poaceae; Competitive endogenous RNA
7.  Genetic Interaction between Tmprss2-ERG Gene Fusion and Nkx3.1-Loss Does Not Enhance Prostate Tumorigenesis in Mouse Models 
PLoS ONE  2015;10(3):e0120628.
Gene fusions involving ETS family transcription factors (mainly TMPRSS2-ERG and TMPRSS2-ETV1 fusions) have been found in ~50% of human prostate cancer cases. Although expression of TMPRSS2-ERG or TMPRSS2-ETV1 fusion alone is insufficient to initiate prostate tumorigenesis, they appear to sensitize prostate epithelial cells for cooperation with additional oncogenic mutations to drive frank prostate adenocarcinoma. To search for such ETS-cooperating oncogenic events, we focused on a well-studied prostate tumor suppressor NKX3.1, as loss of NKX3.1 is another common genetic alteration in human prostate cancer. Previous studies have shown that deletions at 8p21 (harboring NKX3.1) and 21q22 (resulting in TMPRSS2-ERG fusion) were both present in a subtype of prostate cancer cases, and that ERG can lead to epigenetic silencing of NKX3.1 in prostate cancer cells, whereas NKX3.1 can in turn negatively regulate TMPRSS2-ERG fusion expression via suppression of the TMPRSS2 promoter activity. We recently generated knockin mouse models for TMPRSS2-ERG and TMPRSS2-ETV1 fusions, utilizing the endogenous Tmprss2 promoter. We crossed these knockin models to an Nkx3.1 knockout mouse model. In Tmprss2-ERG;Nkx3.1+/- (or -/-) male mice, although we observed a slight but significant upregulation of Tmprss2-ERG fusion expression upon Nkx3.1 loss, we did not detect any significant cooperation between these two genetic events to enhance prostate tumorigenesis in vivo. Furthermore, retrospective analysis of a previously published human prostate cancer dataset revealed that within ERG-overexpressing prostate cancer cases, NKX3.1 loss or deletion did not predict biochemical relapse after radical prostatectomy. Collectively, these data suggest that although TMPRSS2-ERG fusion and loss of NKX3.1 are among the most common mutational events found in prostate cancer, and although each of them can sensitize prostate epithelial cells for cooperating with other oncogenic events, these two events themselves do not appear to cooperate at a significant level in vivo to enhance prostate tumorigenesis.
doi:10.1371/journal.pone.0120628
PMCID: PMC4364018  PMID: 25780911
8.  Novel compounds lowering the cellular isoform of the human prion protein in cultured human cells 
Bioorganic & medicinal chemistry  2014;22(6):1960-1972.
Purpose
Previous studies showed that lowering PrPC concomitantly reduced PrPSc in the brains of mice inoculated with prions. We aimed to develop assays that measure PrPC on the surface of human T98G glioblastoma and IMR32 neuroblastoma cells. Using these assays, we sought to identify chemical hits, confirmed hits, and scaffolds that potently lowered PrPC levels in human brains cells, without lethality, and that could achieve drug concentrations in the brain after oral or intraperitoneal dosing in mice.
Methods
We utilized HTS ELISA assays to identify small compounds that lower PrPC levels by ≥30% on the cell surface of human glioblastoma (T98G) and neuroblastoma (IMR32) cells.
Results
From 44,578 diverse chemical compounds tested, 138 hits were identified by single point confirmation (SPC) representing 7 chemical scaffolds in T98G cells, and 114 SPC hits representing 6 scaffolds found in IMR32 cells. When the confirmed SPC hits were combined with structurally related analogs, >300 compounds (representing 6 distinct chemical scaffolds) were tested for dose-response (EC50) in both cell lines, only studies in T98G cells identified compounds that reduced PrPC without killing the cells. EC50 values from 32 hits ranged from 65 nM to 4.1 μM. Twenty-eight were evaluated in vivo in pharmacokinetic studies after a single 10 mg/kg oral or intraperitoneal dose in mice. Our results showed brain concentrations as high as 16.2 μM, but only after intraperitoneal dosing.
Conclusions
Our studies identified leads for future studies to determine which compounds might lower PrPC levels in rodent brain, and provide the basis of a therapeutic for fatal disorders caused by PrP prions.
doi:10.1016/j.bmc.2014.01.001
PMCID: PMC3984052  PMID: 24530226
prion; PrPC; PrPSc; neurodegeneration; Creutzfeldt-Jakob disease
9.  Temporal changes in MrgC expression after spinal nerve injury 
Neuroscience  2013;261:43-51.
Mas-related G-protein-coupled receptor subtype C (MrgC) may play an important role in pain sensation. However, the distribution of MrgC receptors in different subpopulations of rodent dorsal root ganglion (DRG) neurons has not been clearly demonstrated owing to a lack of MrgC-selectively antibody. It is also unclear whether peripheral nerve injury induces different time-dependent changes in MrgC expression in injured and uninjured DRG neurons. Here we showed that MrgC immunoreactivity is distributed in both IB4-positive (non-peptidergic) and calcitonin gene-related peptide-positive (peptidergic) DRG neurons in mice and rats. Importantly, the MrgC mRNA level and MrgC immunoreactivity were both decreased in the injured L5 DRG compared to corresponding levels in the contralateral (uninjured) DRG in rats on days 14 and 30 after an L5 spinal nerve ligation. In contrast, mRNA and protein levels of MrgC were increased in the adjacent uninjured L4 DRG. Thus, nerve injury may induce temporal changes in MrgC expression that differ between injured and uninjured DRG neurons. In animal behavior tests, chronic constriction injury of the sciatic nerve induced mechanical pain hypersensitivity in wild-type mice and Mrg-clusterΔ−/− mice (Mrg KO). However, the duration of mechanical hypersensitivity was longer in the Mrg KO mice than in their wild-type littermates, indicating that activation of Mrgs may constitute an endogenous mechanism that inhibits the maintenance of neuropathic pain. These findings extend our knowledge about the distribution of MrgC in rodent DRG neurons and the regulation of its expression by nerve injury.
doi:10.1016/j.neuroscience.2013.12.041
PMCID: PMC3945476  PMID: 24374082
MrgC; dorsal root ganglion; neuropathic pain; nerve injury
10.  An Arabidopsis Transcriptional Regulatory Map Reveals Distinct Functional and Evolutionary Features of Novel Transcription Factors 
Molecular Biology and Evolution  2015;32(7):1767-1773.
Transcription factors (TFs) play key roles in both development and stress responses. By integrating into and rewiring original systems, novel TFs contribute significantly to the evolution of transcriptional regulatory networks. Here, we report a high-confidence transcriptional regulatory map covering 388 TFs from 47 families in Arabidopsis. Systematic analysis of this map revealed the architectural heterogeneity of developmental and stress response subnetworks and identified three types of novel network motifs that are absent from unicellular organisms and essential for multicellular development. Moreover, TFs of novel families that emerged during plant landing present higher binding specificities and are preferentially wired into developmental processes and these novel network motifs. Further unveiled connection between the binding specificity and wiring preference of TFs explains the wiring preferences of novel-family TFs. These results reveal distinct functional and evolutionary features of novel TFs, suggesting a plausible mechanism for their contribution to the evolution of multicellular organisms.
doi:10.1093/molbev/msv058
PMCID: PMC4476157  PMID: 25750178
transcription factor; transcriptional regulation; network structure; novel family; wiring preference
11.  cspA Influences Biofilm Formation and Drug Resistance in Pathogenic Fungus Aspergillus fumigatus 
BioMed Research International  2015;2015:960357.
The microbial cell wall plays a crucial role in biofilm formation and drug resistance. cspA encodes a repeat-rich glycophosphatidylinositol-anchored cell wall protein in the pathogenic fungus Aspergillus fumigatus. To determine whether cspA has a significant impact on biofilm development and sensitivity to antifungal drugs in A. fumigatus, a ΔcspA mutant was constructed by targeted gene disruption, and we then reconstituted the mutant to wild type by homologous recombination of a functional cspA gene. Deletion of cspA resulted in a rougher conidial surface, reduced biofilm formation, decreased resistance to antifungal agents, and increased internalization by A549 human lung epithelial cells, suggesting that cspA not only participates in maintaining the integrity of the cell wall, but also affects biofilm establishment, drug response, and invasiveness of A. fumigatus.
doi:10.1155/2015/960357
PMCID: PMC4363613  PMID: 25821832
12.  MrgC agonism at central terminals of primary sensory neurons inhibits neuropathic pain 
Pain  2013;155(3):534-544.
Chronic neuropathic pain is often refractory to current pharmacotherapies. The rodent Mas-related G-protein-coupled receptor subtype C (MrgC) shares substantial homogeneity with its human homolog, MrgX1, and is located specifically in small-diameter dorsal root ganglion (DRG) neurons. However, evidence regarding the role of MrgC in chronic pain conditions has been disparate and inconsistent. Accordingly, the therapeutic value of MrgX1 as a target for pain treatment in humans remains uncertain. Here, we found that intrathecal injection of BAM8-22 (a 15-amino acid peptide MrgC agonist) and JHU58 (a novel dipeptide MrgC agonist) inhibited both mechanical and heat hypersensitivity in rats after an L5 spinal nerve ligation (SNL). Intrathecal JHU58-induced pain inhibition was dose-dependent in SNL rats. Importantly, drug efficacy was lost in Mrg-cluster gene knockout (Mrg KO) mice and was blocked by gene silencing with intrathecal MrgC siRNA and by a selective MrgC receptor antagonist in SNL rats, suggesting that the drug action is MrgC-dependent. Further, in a mouse model of trigeminal neuropathic pain, microinjection of JHU58 into ipsilateral subnucleus caudalis inhibited mechanical hypersensitivity in wild-type but not Mrg KO mice. Finally, JHU58 attenuated the mEPSC frequency both in medullary dorsal horn neurons of mice after trigeminal nerve injury and in lumbar spinal dorsal horn of mice after SNL. We provide multiple lines of evidence that MrgC agonism at spinal but not peripheral sites may constitute a novel pain inhibitory mechanism that involves inhibition of peripheral excitatory inputs onto postsynaptic dorsal horn neurons in different rodent models of neuropathic pain.
doi:10.1016/j.pain.2013.12.008
PMCID: PMC3945061  PMID: 24333779
MrgC; dorsal root ganglion; spinal cord; neuropathic pain; analgesia
13.  Low-Cost Photolithographic Fabrication of Nanowires and Microfilters for Advanced Bioassay Devices 
Sensors (Basel, Switzerland)  2015;15(3):6091-6104.
Integrated microfluidic devices with nanosized array electrodes and microfiltration capabilities can greatly increase sensitivity and enhance automation in immunoassay devices. In this contribution, we utilize the edge-patterning method of thin aluminum (Al) films in order to form nano- to micron-sized gaps. Evaporation of high work-function metals (i.e., Au, Ag, etc.) on these gaps, followed by Al lift-off, enables the formation of electrical uniform nanowires from low-cost, plastic-based, photomasks. By replacing Al with chromium (Cr), the formation of high resolution, custom-made photomasks that are ideal for low-cost fabrication of a plurality of array devices were realized. To demonstrate the feasibility of such Cr photomasks, SU-8 micro-pillar masters were formed and replicated into PDMS to produce micron-sized filters with 3–4 µm gaps and an aspect ratio of 3. These microfilters were capable of retaining 6 µm beads within a localized site, while allowing solvent flow. The combination of nanowire arrays and micro-pillar filtration opens new perspectives for rapid R&D screening of various microfluidic-based immunoassay geometries, where analyte pre-concentration and highly sensitive, electrochemical detection can be readily co-localized.
doi:10.3390/s150306091
PMCID: PMC4435220  PMID: 25774709
nanowire; nanogaps; microelectrode arrays; sensor; immunoassay; microfluidic; photolithography; isotropic etching
15.  Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain 
Neuron  2014;81(4):873-887.
SUMMARY
The peripheral terminals of primary nociceptive neurons play an essential role in pain detection mediated by membrane receptors like TRPV1, a molecular sensor of heat and capsaicin. However, the contribution of central terminal TRPV1 in the dorsal horn to chronic pain has not been investigated directly. Combining primary sensory neuron-specific GCaMP3 imaging with a trigeminal neuropathic pain model, we detected robust neuronal hyperactivity in injured and uninjured nerves in the skin, soma in trigeminal ganglion, and central terminals in the spinal trigeminal nucleus. Extensive TRPV1 hyperactivity was observed in central terminals innervating all dorsal horn laminae. The central terminal TRPV1 sensitization was maintained by descending serotonergic (5-HT) input from the brainstem. Central blockade of TRPV1 or 5-HT/5-HT3A receptors attenuated central terminal sensitization, excitatory primary afferent inputs, and mechanical hyperalgesia in the territories of injured and uninjured nerves. Our results reveal new central mechanisms facilitating central terminal sensitization underlying chronic pain.
doi:10.1016/j.neuron.2013.12.011
PMCID: PMC3943838  PMID: 24462040
16.  Aurora B-dependent phosphorylation of Ataxin-10 promotes the interaction between Ataxin-10 and Plk1 in cytokinesis 
Scientific Reports  2015;5:8360.
Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurologic disorder caused by ATTCT expansion in the ATXN10 gene. Previous investigations have identified that depletion of Ataxin-10, the gene product, leads to cellular apoptosis and cytokinesis failure. Herein we identify the mitotic kinase Aurora B as an Ataxin-10 interacting partner. Aurora B interacts with and phosphorylates Ataxin-10 at S12, as evidenced by in vitro kinase and mass spectrometry analysis. Both endogenous and S12-phosphorylated Ataxin-10 localizes to the midbody during cytokinesis, and cytokinetic defects induced by inhibition of ATXN10 expression is not rescued by the S12A mutant. Inhibition of Aurora B or expression of the S12A mutant renders reduced interaction between Ataxin-10 and polo-like kinase 1 (Plk1), a kinase previously identified to regulate Ataxin-10 in cytokinesis. Taken together, we propose a model that Aurora B phosphorylates Ataxin-10 at S12 to promote the interaction between Ataxin-10 and Plk1 in cytokinesis. These findings identify an Aurora B-dependent mechanism that implicates Ataxin-10 in cytokinesis.
doi:10.1038/srep08360
PMCID: PMC4322367  PMID: 25666058
17.  Basal cell signaling by p63 controls luminal progenitor function and lactation via NRG1 
Developmental cell  2014;28(2):147-160.
Summary
The mammary epithelium is organized as a bi-layer of luminal and basal/myoepithelial cells. During pregnancy the luminal compartment expands for milk production, while basal cells are thought to provide structural and contractile support. Here we reveal an unanticipated, pregnancy-specific role of basal epithelia as a central coordinator of lactogenesis. We demonstrate that genetic deletion of the transcription factor p63 (Trp63) gene exclusively within basal cells of the adult gland during pregnancy leads to dramatic defects in luminal cell proliferation and differentiation, resulting in lactation failure. This phenotype is explained by direct transcriptional activation of the EGF-family ligand gene Nrg1 by p63 selectively in basal cells, which is required for luminal ERBB4/STAT5A activation and consequent luminal progenitor cell maturation. Thus, paracrine basal-to-luminal cell signaling, controlled by p63 via NRG1, orchestrates the entire lactation program. Collectively, these findings redefine the paradigm for cellular interactions specifying the functional maturation of the mammary gland.
doi:10.1016/j.devcel.2013.11.019
PMCID: PMC3951056  PMID: 24412575
p63; basal cell; paracrine signaling; lactation; luminal progenitor cells
18.  Human cervical cancer oncogene-1 over expression in colon cancer and its clinical significance 
Objective: This study was to explore the expression of human cervical cancer oncogene-1 (HCCR-1) in colon cancer and its clinical significance. Methods: RT-PCR, immunohistochemistry and Western blot assay were employed to detect HCCR-1 expression in 152 colon cancers, 43 adjacent non-cancerous tissues and 37 normal tissues. In addition, immunohistochemistry was done to detect CEA in colon cancers. Results: The mRNA expression of HCCR-1 in colon cancers was higher than that in the adjacent non-cancerous tissues (P < 0.05), and the mRNA expression of HCCR-1 in adjacent non-cancerous tissues was higher than that in normal tissues (P < 0.05). The positive rate of HCCR-1 in colon cancers was 80.9%, which was higher than that in adjacent non-cancerous tissues (P < 0.05). Almost no HCCR-1 expression was observed in normal tissues, weak expression in adjacent non-cancerous tissues and strong expression in colon cancers. The positive rate of HCCR-1 in colon cancer at Duke stage B-C was 87.3%, which was higher than that in stage A colon cancer (63.6%, P < 0.05). Conclusion: HCCR-1 is over-expressed in colon cancers, indicating that HCCR-1 may participate in occurrence and development of colon cancer and has a correlation with the pathological progress of colon cancer progression.
PMCID: PMC4358534  PMID: 25785079
Colonic cancer; gene expression; gene; human cervical cancer oncogene-1
19.  Calpain 2 Activation of P-TEFb Drives Megakaryocyte Morphogenesis and Is Disrupted by Leukemogenic GATA1 Mutation 
Developmental cell  2013;27(6):607-620.
SUMMARY
Megakaryocyte morphogenesis employs a “hypertrophy-like” developmental program, dependent on P-TEFb kinase activation and cytoskeletal remodeling. P-TEFb activation classically occurs by a feedback regulated process of signal-induced, reversible release of active Cdk9-cyclin T modules from large inactive 7SK snRNP complexes. Here we have identified an alternative pathway of irreversible P-TEFb activation in megakaryopoiesis, mediated by dissolution of the 7SK snRNP complex. In this pathway calpain 2 cleavage of the core 7SK snRNP component MePCE promoted P-TEFb release and consequent upregulation of a cohort of cytoskeleton remodeling factors, including α-actinin-1. In a subset of human megakaryocytic leukemias, the transcription factor GATA1 undergoes truncating mutation (GATA1s). Here we linked the GATA1s mutation to defects in megakaryocytic upregulation of calpain 2 and of P-TEFb-dependent cytoskeletal remodeling factors. Restoring calpain 2 expression in GATA1s-mutant megakaryocytes rescued normal development, implicating this morphogenetic pathway as a target in human leukemogenesis.
doi:10.1016/j.devcel.2013.11.013
PMCID: PMC3892434  PMID: 24369834
megakaryopoiesis; P-TEFb; 7SK snRNP; calpain 2; GATA1s mutant
20.  Antiprion compounds that reduce PrPSc levels in dividing and stationary-phase cells 
Bioorganic & medicinal chemistry  2013;21(24):7999-8012.
During prion diseases, a normally benign, host protein, denoted PrPC, undergoes alternative folding into the aberrant isoform, PrPSc. We used ELISA assays to identify and confirm hits in order to develop leads that reduce PrPSc in prion-infected dividing and stationary-phase mouse neuroblastoma (ScN2a-cl3) cells. We tested 52,830 diverse small molecules in dividing cells and 49,430 in stationary-phase cells. This led to 3,100 HTS and 970 single point confirmed (SPC) hits in dividing cells, 331 HTS and 55 confirmed SPC hits in stationary-phase cells as well as 36 confirmed SPC hits active in both. Fourteen chemical leads were identified from confirmed SPC hits in dividing cells and three in stationary-phase cells. From more than 682 compounds tested in concentration-effect relationships in dividing cells to determine potency (EC50), 102 had EC50 values between 1–10 µM and 50 had EC50 values of <1 µM; none affected cell viability. We observed an excellent correlation between EC50 values determined by ELISA and Western immunoblotting for 28 representative compounds in dividing cells (R2 = 0.75; p < 0.0001). Of the 55 confirmed SPC hits in stationary-phase cells, 23 were piperazine, indole, or urea leads. The potency (EC50) of one indole in stationary-phase and dividing ScN2a-cl3 cells was 7.5 and 1.6 µM, respectively. Unexpectedly, the number of hits in stationary-phase cells was ~10% of that in dividing cells. The explanation for this difference remains to be determined.
doi:10.1016/j.bmc.2013.09.022
PMCID: PMC3984054  PMID: 24183589
Antiprion compounds; PrPSc; dividing and stationary-phase brain cells
21.  Imaging orofacial pain in mice 
Molecular Pain  2014;10(Suppl 1):O2.
doi:10.1186/1744-8069-10-S1-O2
PMCID: PMC4304368
22.  GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia 
Leukemia  2013;28(6):1259-1270.
Transient leukemia (TL) is evident in 5–10% of all neonates with Down syndrome (DS) and associated with N-terminal truncating GATA1-mutations (GATA1s). Here we report that TL cell clones generate abundant eosinophils in a substantial fraction of patients. Sorted eosinophils from patients with TL and eosinophilia carried the same GATA1s-mutation as sorted TL-blasts, consistent with their clonal origin. TL-blasts exhibited a genetic program characteristic of eosinophils and differentiated along the eosinophil lineage in vitro. Similarly, ectopic expression of Gata1s, but not Gata1, in wild-type CD34+-hematopoietic stem and progenitor cells induced hyperproliferation of eosinophil promyelocytes in vitro. While GATA1s retained the function of GATA1 to induce eosinophil genes by occupying their promoter regions, GATA1s was impaired in its ability to repress oncogenic MYC and the pro-proliferative E2F transcription network. ChIP-seq indicated reduced GATA1s occupancy at the MYC promoter. Knockdown of MYC, or the obligate E2F-cooperation partner DP1, rescued the GATA1s-induced hyperproliferative phenotype. In agreement, terminal eosinophil maturation was blocked in Gata1Δe2 knockin mice, exclusively expressing Gata1s, leading to accumulation of eosinophil precursors in blood and bone marrow. These data suggest a direct relationship between the N-terminal truncating mutations of GATA1 and clonal eosinophilia in DS patients.
doi:10.1038/leu.2013.373
PMCID: PMC4047213  PMID: 24336126
Down syndrome; eosinophilia; GATA1s; MYC; E2F
23.  Enhancing Fullerene-Based Solar Cell Lifetimes by Addition of a Fullerene Dumbbell** 
Cost-effective, solution-processable organic photovoltaics (OPV) present an interesting alternative to inorganic silicon-based solar cells. However, one of the major remaining challenges of OPV devices is their lack of long-term operational stability, especially at elevated temperatures. The synthesis of a fullerene dumbbell and its use as an additive in the active layer of a PCDTBT:PCBM-based OPV device is reported. The addition of only 20 % of this novel fullerene not only leads to improved device efficiencies, but more importantly also to a dramatic increase in morphological stability under simulated operating conditions. Dynamic secondary ion mass spectrometry (DSIMS) and TEM are used, amongst other techniques, to elucidate the origins of the improved morphological stability.
doi:10.1002/anie.201407310
PMCID: PMC4241035  PMID: 25264304
fullerenes; lifetime; organic solar cells; photovoltaics; stability
24.  RUNX1, a transcription factor mutated in breast cancer, controls the fate of ER-positive mammary luminal cells 
eLife  null;3:e03881.
RUNX1 encodes a RUNX family transcription factor (TF) and was recently identified as a novel mutated gene in human luminal breast cancers. We found that Runx1 is expressed in all subpopulations of murine mammary epithelial cells (MECs) except the secretory alveolar luminal cells. Conditional knockout of Runx1 in MECs by MMTV-Cre led to a decrease in luminal MECs, largely due to a profound reduction in the estrogen receptor (ER)-positive mature luminal subpopulation, a phenotype that could be rescued by the loss of either Trp53 or Rb1. Mechanistically RUNX1 represses Elf5, a master regulatory TF gene for alveolar cells, and regulates mature luminal TF/co-factor genes (e.g., Foxa1 and Cited1) involved in the ER program. Collectively, our data identified a key regulator of the ER+ luminal lineage whose disruption may contribute to the development of ER+ luminal breast cancer when under the background of either TP53 or RB1 loss.
DOI: http://dx.doi.org/10.7554/eLife.03881.001
eLife digest
Stem cells can develop into the many types of specialized cell found in the body. Several proteins regulate these transformations by switching on and off the expression of genes that are specific to different cell types. Disrupting these proteins can cause the development of cells to go awry and can lead to cancer.
A protein called RUNX1 controls gene expression to direct the development of blood cells. Mutations in the gene encoding this protein have been linked to blood cancers and a particular type of breast cancer, which begins in the cells that line the ducts that carry milk towards the nipple.
Mammary duct-lining cells develop from a pool of stem cells that produces breast tissue cells. Now van Bragt et al. have found that RUNX1 is expressed in the cells lining the ducts of the mammary glands, except those that produce milk. Deleting the gene for RUNX1 in mice reduced the number of duct-lining cells, especially a subgroup of cells that are the sensors for the hormone estrogen. Through experiments on breast cancer cells, van Bragt et al. found that RUNX1 is able to dictate the fate of duct-lining breast cells by controlling other protein regulators. RUNX1 boosts the activity of at least one regulator that encourages the cells to become duct-lining cells and represses another regulatory protein that turns cells into milk-producing cells.
Next, van Bragt et al. found that, in mice lacking the gene for RUNX1, reducing the amounts of certain proteins that normally suppress the formation of tumors restored the populations of estrogen-sensing duct-lining cells. This suggests that mutations in the gene encoding RUNX1, coupled with the loss of a tumor-suppressing protein, may contribute to the development of cancer in the cells that line the breast ducts.
The next challenge is to determine exactly how RUNX1 mutations work together with the loss of the tumor-suppressing protein to drive breast cancer development. This knowledge may translate into new approaches to prevent or treat this type of breast cancer.
DOI: http://dx.doi.org/10.7554/eLife.03881.002
doi:10.7554/eLife.03881
PMCID: PMC4381933  PMID: 25415051
RUNX1; cell fate; master regulatory transcription factor; estrogen receptor; ELF5; luminal breast cancer; human; mouse
25.  Topological transport and atomic tunnelling–clustering dynamics for aged Cu-doped Bi2Te3 crystals 
Nature Communications  2014;5:5022.
Enhancing the transport contribution of surface states in topological insulators is vital if they are to be incorporated into practical devices. Such efforts have been limited by the defect behaviour of Bi2Te3 (Se3) topological materials, where the subtle bulk carrier from intrinsic defects is dominant over the surface electrons. Compensating such defect carriers is unexpectedly achieved in (Cu0.1Bi0.9)2Te3.06 crystals. Here we report the suppression of the bulk conductance of the material by four orders of magnitude by intense ageing. The weak antilocalization analysis, Shubnikov–de Haas oscillations and scanning tunnelling spectroscopy corroborate the transport of the topological surface states. Scanning tunnelling microscopy reveals that Cu atoms are initially inside the quintuple layers and migrate to the layer gaps to form Cu clusters during the ageing. In combination with first-principles calculations, an atomic tunnelling–clustering picture across a diffusion barrier of 0.57 eV is proposed.
Enhancing the transport properties of surface states in topological insulators is vital if they are to be incorporated into practical devices. Towards this end, Chen et al. study the transport in aged (Cu0.1Bi0.9)2Te3.06, where the ageing process suppresses bulk conductance by up to four orders of magnitude.
doi:10.1038/ncomms6022
PMCID: PMC4199107  PMID: 25247692

Results 1-25 (107)