4,236 research outputs found
Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology.
Tuberculosis remains a global pandemic and drives lung matrix destruction to transmit. Whilst pathways driving inflammatory responses in macrophages have been relatively well described, negative regulatory pathways are less well defined. We hypothesised that Mycobacterium tuberculosis (Mtb) specifically targets negative regulatory pathways to augment immunopathology. Inhibition of signalling through the PI3K/AKT/mTORC1 pathway increased matrix metalloproteinase-1 (MMP-1) gene expression and secretion, a collagenase central to TB pathogenesis, and multiple pro-inflammatory cytokines. In patients with confirmed pulmonary TB, PI3Kδ expression was absent within granulomas. Furthermore, Mtb infection suppressed PI3Kδ gene expression in macrophages. Interestingly, inhibition of the MNK pathway, downstream of pro-inflammatory p38 and ERK MAPKs, also increased MMP-1 secretion, whilst suppressing secretion of TH1 cytokines. Cross-talk between the PI3K and MNK pathways was demonstrated at the level of eIF4E phosphorylation. Mtb globally suppressed the MMP-inhibitory pathways in macrophages, reducing levels of mRNAs encoding PI3Kδ, mTORC-1 and MNK-1 via upregulation of miRNAs. Therefore, Mtb disrupts negative regulatory pathways at multiple levels in macrophages to drive a tissue-destructive phenotype that facilitates transmission
A simple and robust method for connecting small-molecule drugs using gene-expression signatures
Interaction of a drug or chemical with a biological system can result in a
gene-expression profile or signature characteristic of the event. Using a
suitably robust algorithm these signatures can potentially be used to connect
molecules with similar pharmacological or toxicological properties. The
Connectivity Map was a novel concept and innovative tool first introduced by
Lamb et al to connect small molecules, genes, and diseases using genomic
signatures [Lamb et al (2006), Science 313, 1929-1935]. However, the
Connectivity Map had some limitations, particularly there was no effective
safeguard against false connections if the observed connections were considered
on an individual-by-individual basis. Further when several connections to the
same small-molecule compound were viewed as a set, the implicit null hypothesis
tested was not the most relevant one for the discovery of real connections.
Here we propose a simple and robust method for constructing the reference
gene-expression profiles and a new connection scoring scheme, which importantly
allows the valuation of statistical significance of all the connections
observed. We tested the new method with the two example gene-signatures (HDAC
inhibitors and Estrogens) used by Lamb et al and also a new gene signature of
immunosuppressive drugs. Our testing with this new method shows that it
achieves a higher level of specificity and sensitivity than the original
method. For example, our method successfully identified raloxifene and
tamoxifen as having significant anti-estrogen effects, while Lamb et al's
Connectivity Map failed to identify these. With these properties our new method
has potential use in drug development for the recognition of pharmacological
and toxicological properties in new drug candidates.Comment: 8 pages, 2 figures, and 2 tables; supplementary data supplied as a
ZIP fil
State Transfer Between a Mechanical Oscillator and Microwave Fields in the Quantum Regime
Recently, macroscopic mechanical oscillators have been coaxed into a regime
of quantum behavior, by direct refrigeration [1] or a combination of
refrigeration and laser-like cooling [2, 3]. This exciting result has
encouraged notions that mechanical oscillators may perform useful functions in
the processing of quantum information with superconducting circuits [1, 4-7],
either by serving as a quantum memory for the ephemeral state of a microwave
field or by providing a quantum interface between otherwise incompatible
systems [8, 9]. As yet, the transfer of an itinerant state or propagating mode
of a microwave field to and from a mechanical oscillator has not been
demonstrated owing to the inability to agilely turn on and off the interaction
between microwave electricity and mechanical motion. Here we demonstrate that
the state of an itinerant microwave field can be coherently transferred into,
stored in, and retrieved from a mechanical oscillator with amplitudes at the
single quanta level. Crucially, the time to capture and to retrieve the
microwave state is shorter than the quantum state lifetime of the mechanical
oscillator. In this quantum regime, the mechanical oscillator can both store
and transduce quantum information
A habituation account of change detection in same/different judgments
We investigated the basis of change detection in a short-term priming task. In two experiments, participants were asked to indicate whether or not a target word was the same as a previously presented cue. Data from an experiment measuring magnetoencephalography failed to find different patterns for “same” and “different” responses, consistent with the claim that both arise from a common neural source, with response magnitude defining the difference between immediate novelty versus familiarity. In a behavioral experiment, we tested and confirmed the predictions of a habituation account of these judgments by comparing conditions in which the target, the cue, or neither was primed by its presentation in the previous trial. As predicted, cue-primed trials had faster response times, and target-primed trials had slower response times relative to the neither-primed baseline. These results were obtained irrespective of response repetition and stimulus–response contingencies. The behavioral and brain activity data support the view that detection of change drives performance in these tasks and that the underlying mechanism is neuronal habituation
Prognostic and therapeutic significance of carbohydrate antigen 19-9 as tumor marker in patients with pancreatic cancer
In pancreatic cancer ( PC) accurate determination of treatment response by imaging often remains difficult. Various efforts have been undertaken to investigate new factors which may serve as more appropriate surrogate parameters of treatment efficacy. This review focuses on the role of carbohydrate antigen 19- 9 ( CA 19- 9) as a prognostic tumor marker in PC and summarizes its contribution to monitoring treatment efficacy. We undertook a Medline/ PubMed literature search to identify relevant trials that had analyzed the prognostic impact of CA 19- 9 in patients treated with surgery, chemoradiotherapy and chemotherapy for PC. Additionally, relevant abstract publications from scientific meetings were included. In advanced PC, pretreatment CA 19- 9 levels have a prognostic impact regarding overall survival. Also a CA 19- 9 decline under chemotherapy can provide prognostic information for median survival. A 20% reduction of CA 19- 9 baseline levels within the first 8 weeks of chemotherapy appears to be sufficient to define a prognostic relevant subgroup of patients ('CA 19- 9 responder'). It still remains to be defined whether the CA 19- 9 response is a more reliable method for evaluating treatment efficacy compared to conventional imaging. Copyright (c) 2006 S. Karger AG, Basel
30 inch Roll-Based Production of High-Quality Graphene Films for Flexible Transparent Electrodes
We report that 30-inch scale multiple roll-to-roll transfer and wet chemical
doping considerably enhance the electrical properties of the graphene films
grown on roll-type Cu substrates by chemical vapor deposition. The resulting
graphene films shows a sheet resistance as low as ~30 Ohm/sq at ~90 %
transparency which is superior to commercial transparent electrodes such as
indium tin oxides (ITO). The monolayer of graphene shows sheet resistances as
low as ~125 Ohm/sq with 97.4% optical transmittance and half-integer quantum
Hall effect, indicating the high-quality of these graphene films. As a
practical application, we also fabricated a touch screen panel device based on
the graphene transparent electrodes, showing extraordinary mechanical and
electrical performances
Non-small cell lung carcinoma in an adolescent manifested by acute paraplegia due to spinal metastases: a case report
<p>Abstract</p> <p>Introduction</p> <p>Bronchial carcinomas in childhood and adolescence are extremely rare; only individual cases have been reported previously.</p> <p>Case presentation</p> <p>We report on a 16-year-old Caucasian German boy with non-small cell lung carcinoma (squamous cell non-small cell lung carcinoma) stage IV, T4N2M1, without epidermal growth factor receptor overexpression and/or mutation or k-ras mutation. He presented with paraplegia due to spinal metastases of the bronchial carcinoma. No familial predisposition or toxin exposure was identified. Treatment following adult protocols consisted of surgical intervention for spinal metastases, first-line cisplatinum and gemcitabine, irradiation and second-line docetaxel. After a transient response our patient experienced disease progression and died about 10 months later.</p> <p>Conclusion</p> <p>Response and survival in our 16-year-old patient were similar to adult patients with stage IV non-small cell lung carcinoma.</p
Longer telomere length in peripheral white blood cells is associated with risk of lung cancer and the rs2736100 (CLPTM1L-TERT) polymorphism in a prospective cohort study among women in China.
A recent genome-wide association study of lung cancer among never-smoking females in Asia demonstrated that the rs2736100 polymorphism in the TERT-CLPTM1L locus on chromosome 5p15.33 was strongly and significantly associated with risk of adenocarcinoma of the lung. The telomerase gene TERT is a reverse transcriptase that is critical for telomere replication and stabilization by controlling telomere length. We previously found that longer telomere length measured in peripheral white blood cell DNA was associated with increased risk of lung cancer in a prospective cohort study of smoking males in Finland. To follow up on this finding, we carried out a nested case-control study of 215 female lung cancer cases and 215 female controls, 94% of whom were never-smokers, in the prospective Shanghai Women's Health Study cohort. There was a dose-response relationship between tertiles of telomere length and risk of lung cancer (odds ratio (OR), 95% confidence interval [CI]: 1.0, 1.4 [0.8-2.5], and 2.2 [1.2-4.0], respectively; P trend = 0.003). Further, the association was unchanged by the length of time from blood collection to case diagnosis. In addition, the rs2736100 G allele, which we previously have shown to be associated with risk of lung cancer in this cohort, was significantly associated with longer telomere length in these same study subjects (P trend = 0.030). Our findings suggest that individuals with longer telomere length in peripheral white blood cells may have an increased risk of lung cancer, but require replication in additional prospective cohorts and populations
RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord
ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned \u3e50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG’s). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network “hub” gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF’s involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful in ALS patients
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