Diagnostic Value of Lumbar Facet Joint Injection: A Prospective Triple Cross-Over Study

The diagnosis “lumbar facet syndrome” is common and often indicates severe lumbar spine surgery procedures. It is doubtful whether a painful facet joint (FJ) can be identified by a single FJ block. The aim of this study was to clarify the validity of a single and placebo controlled bilateral FJ blocks using local anesthetics. A prospective single blinded triple cross-over study was performed. 60 patients (31 f, 29 m, mean age 53.2 yrs (22–73)) with chronic low back pain (mean pain persistance 31 months, 6 months of conservative treatment without success) admitted to a local orthopaedic department for surgical or conservative therapy of chronic LBP, were included in the study. Effect on pain reduction (10 point rating scale) was measured. The 60 subjects were divided into six groups with three defined sequences of fluoroscopically guided bilateral monosegmental lumbar FJ test injections in “oblique needle” technique: verum-(local anaesthetic-), placebo-(sodium chloride-) and sham-injection. Carry-over and periodic effects were evaluated and a descriptive and statistical analysis regarding the effectiveness, difference and equality of the FJ injections and the different responses was performed. The results show a high rate of non-response, which documents the lack of reliable and valid predictors for a positive response towards FJ blocks. There was a high rate of placebo reactions noted, including subjects who previously or later reacted positively to verum injections. Equivalence was shown among verum vs. placebo and partly vs. sham also. With regard to test validity criteria, a single intraarticular FJ block with local anesthetics is not useful to detect the pain-responsible FJ and therefore is no valid and reliable diagostic tool to specify indication of lumbar spine surgery. Comparative FJ blocks with local anesthetics and placebo-controls have to be interpretated carefully also, because they solely give no proper diagnosis on FJ being main pain generator

MNS1 Is Essential for Spermiogenesis and Motile Ciliary Functions in Mice

During spermiogenesis, haploid round spermatids undergo dramatic cell differentiation and morphogenesis to give rise to mature spermatozoa for fertilization, including nuclear elongation, chromatin remodeling, acrosome formation, and development of flagella. The molecular mechanisms underlining these fundamental processes remain poorly understood. Here, we report that MNS1, a coiled-coil protein of unknown function, is essential for spermiogenesis. We find that MNS1 is expressed in the germ cells in the testes and localizes to sperm flagella in a detergent-resistant manner, indicating that it is an integral component of flagella. MNS1–deficient males are sterile, as they exhibit a sharp reduction in sperm production and the remnant sperm are immotile with abnormal short tails. In MNS1–deficient sperm flagella, the characteristic arrangement of “9+2” microtubules and outer dense fibers are completely disrupted. In addition, MNS1–deficient mice display situs inversus and hydrocephalus. MNS1–deficient tracheal motile cilia lack some outer dynein arms in the axoneme. Moreover, MNS1 monomers interact with each other and are able to form polymers in cultured somatic cells. These results demonstrate that MNS1 is essential for spermiogenesis, the assembly of sperm flagella, and motile ciliary functions

Optimization of Energy-Consuming Pathways towards Rapid Growth in HPV-Transformed Cells

Cancer is a complex, multi-step process characterized by misregulated signal transduction and altered metabolism. Cancer cells divide faster than normal cells and their growth rates have been reported to correlate with increased metabolic flux during cell transformation. Here we report on progressive changes in essential elements of the biochemical network, in an in vitro model of transformation, consisting of primary human keratinocytes, human keratinocytes immortalized by human papillomavirus 16 (HPV16) and passaged repeatedly in vitro, and the extensively-passaged cells subsequently treated with the carcinogen benzo[a]pyrene. We monitored changes in cell growth, cell size and energy metabolism. The more transformed cells were smaller and divided faster, but the cellular energy flux was unchanged. During cell transformation the protein synthesis network contracted, as shown by the reduction in key cap-dependent translation factors. Moreover, there was a progressive shift towards internal ribosome entry site (IRES)-dependent translation. The switch from cap to IRES-dependent translation correlated with progressive activation of c-Src, an activator of AMP-activated protein kinase (AMPK), which controls energy-consuming processes, including protein translation. As cellular protein synthesis is a major energy-consuming process, we propose that the reduction in cell size and protein amount provide energy required for cell survival and proliferation. The cap to IRES-dependent switch seems to be part of a gradual optimization of energy-consuming mechanisms that redirects cellular processes to enhance cell growth, in the course of transformation

Improving the design of industrial microwave processing systems through prediction of the dielectric properties of complex multi-layered materials

Rigorous design of industrial microwave processing systems requires in-depth knowledge of the dielectric properties of the materials to be processed. These values are not easy to measure, particularly when a material is multi-layered containing multiple phases, when one phase has a much higher loss than the other and the application is based on selective heating. This paper demonstrates the ability of the Clausius-Mossotti (CM) model to predict the dielectric constant of multi-layered materials. Furthermore, mixing rules and graphical extrapolation techniques were used to further evidence our conclusions and to estimate the loss factor. The material used for this study was vermiculite, a layered alumina-silicate mineral containing up to 10 % of an interlayer hydrated phase. It was measured at different bulk densities at two distinct microwave frequencies, namely 934 and 2143 MHz. The CM model, based on the ionic polarisability of the bulk material, gives only a prediction of the dielectric constant for experimental data with a deviation of less than 5 % at microwave frequencies. The complex refractive index model (CRIM), Landau, Lifshitz and Loyenga (LLL), Goldschmidt, Böttcher and Bruggeman-Hanai model equations are then shown to give a strong estimation of both dielectric constant and loss factor of the solid material compared to that of the measured powder with a deviation of less than 1 %. Results obtained from this work provide a basis for the design of further electromagnetic processing systems for multi-layered materials consisting of both high loss and low loss components

A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development.

International audienceNFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are incompletely characterized. Here we show a developmental stage-specific differential expression pattern of Nfatc1 driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibit only P2 promoter-derived Nfatc1beta expression, preTCR-positive thymocytes express both Nfatc1beta and P1 promoter-derived Nfatc1alpha transcripts. Inducing NFATc1alpha activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1beta from P2 promoter impairs thymocyte development resulting in severe T-cell lymphopenia. In addition, we show that NFATc1 activity suppresses the B-lineage potential of immature thymocytes, and consolidates their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity is vital in facilitating T-cell differentiation and to prevent Notch3-induced T-acute lymphoblastic leukaemia. Altogether, our results show NFATc1 activity is crucial in determining the T-cell fate of thymocytes

Chemical tagging with APOGEE: discovery of a large population of N-rich stars in the inner Galaxy

Formation of globular clusters (GCs), the Galactic bulge, or galaxy bulges in general is an important unsolved problem in Galactic astronomy. Homogeneous infrared observations of large samples of stars belonging to GCs and the Galactic bulge field are one of the best ways to study these problems. We report the discovery by APOGEE (Apache Point Observatory Galactic Evolution Experiment) of a population of field stars in the inner Galaxy with abundances of N, C, and Al that are typically found in GC stars. The newly discovered stars have high [N/Fe], which is correlated with [Al/Fe] and anticorrelated with [C/Fe]. They are homogeneously distributed across, and kinematically indistinguishable from, other field stars within the same volume. Their metallicity distribution is seemingly unimodal, peaking at [Fe/H] ∼ −1, thus being in disagreement with that of the Galactic GC system. Our results can be understood in terms of different scenarios. N-rich stars could be former members of dissolved GCs, in which case the mass in destroyed GCs exceeds that of the surviving GC system by a factor of ∼8. In that scenario, the total mass contained in so-called ‘first-generation’ stars cannot be larger than that in ‘second-generation’ stars by more than a factor of ∼9 and was certainly smaller. Conversely, our results may imply the absence of a mandatory genetic link between ‘second-generation’ stars and GCs. Last, but not least, N-rich stars could be the oldest stars in the Galaxy, the by-products of chemical enrichment by the first stellar generations formed in the heart of the Galaxy

The Interplay between NF-kappaB and E2F1 Coordinately Regulates Inflammation and Metabolism in Human Cardiac Cells

Pyruvate dehydrogenase kinase 4 (PDK4) inhibition by nuclear factor-κB (NF-κB) is related to a shift towards increased glycolysis during cardiac pathological processes such as cardiac hypertrophy and heart failure. The transcription factors estrogen-related receptor-α (ERRα) and peroxisome proliferator-activated receptor (PPAR) regulate PDK4 expression through the potent transcriptional coactivator PPARγ coactivator-1α (PGC-1α). NF-κB activation in AC16 cardiac cells inhibit ERRα and PPARβ/δ transcriptional activity, resulting in reduced PGC-1α and PDK4 expression, and an enhanced glucose oxidation rate. However, addition of the NF-κB inhibitor parthenolide to these cells prevents the downregulation of PDK4 expression but not ERRα and PPARβ/δ DNA binding activity, thus suggesting that additional transcription factors are regulating PDK4. Interestingly, a recent study has demonstrated that the transcription factor E2F1, which is crucial for cell cycle control, may regulate PDK4 expression. Given that NF-κB may antagonize the transcriptional activity of E2F1 in cardiac myocytes, we sought to study whether inflammatory processes driven by NF-κB can downregulate PDK4 expression in human cardiac AC16 cells through E2F1 inhibition. Protein coimmunoprecipitation indicated that PDK4 downregulation entailed enhanced physical interaction between the p65 subunit of NF-κB and E2F1. Chromatin immunoprecipitation analyses demonstrated that p65 translocation into the nucleus prevented the recruitment of E2F1 to the PDK4 promoter and its subsequent E2F1-dependent gene transcription. Interestingly, the NF-κB inhibitor parthenolide prevented the inhibition of E2F1, while E2F1 overexpression reduced interleukin expression in stimulated cardiac cells. Based on these findings, we propose that NF-κB acts as a molecular switch that regulates E2F1-dependent PDK4 gene transcription

Encoding optical control in LCK kinase to quantitatively investigate its activity in live cells.

LCK is a tyrosine kinase that is essential for initiating T-cell antigen receptor (TCR) signaling. A complete understanding of LCK function is constrained by a paucity of methods to quantitatively study its function within live cells. To address this limitation, we generated LCK*, in which a key active-site lysine is replaced by a photocaged equivalent, using genetic code expansion. This strategy enabled fine temporal and spatial control over kinase activity, thus allowing us to quantify phosphorylation kinetics in situ using biochemical and imaging approaches. We find that autophosphorylation of the LCK active-site loop is indispensable for its catalytic activity and that LCK can stimulate its own activation by adopting a more open conformation, which can be modulated by point mutations. We then show that CD4 and CD8, T-cell coreceptors, can enhance LCK activity, thereby helping to explain their effect in physiological TCR signaling. Our approach also provides general insights into SRC-family kinase dynamics

A meta-analysis reveals the commonalities and differences in Arabidopsis thaliana response to different viral pathogens

Understanding the mechanisms by which plants trigger host defenses in response to viruses has been a challenging problem owing to the multiplicity of factors and complexity of interactions involved. The advent of genomic techniques, however, has opened the possibility to grasp a global picture of the interaction. Here, we used Arabidopsis thaliana to identify and compare genes that are differentially regulated upon infection with seven distinct (+)ssRNA and one ssDNA plant viruses. In the first approach, we established lists of genes differentially affected by each virus and compared their involvement in biological functions and metabolic processes. We found that phylogenetically related viruses significantly alter the expression of similar genes and that viruses naturally infecting Brassicaceae display a greater overlap in the plant response. In the second approach, virus-regulated genes were contextualized using models of transcriptional and protein-protein interaction networks of A. thaliana. Our results confirm that host cells undergo significant reprogramming of their transcriptome during infection, which is possibly a central requirement for the mounting of host defenses. We uncovered a general mode of action in which perturbations preferentially affect genes that are highly connected, central and organized in modules. © 2012 Rodrigo et al.This work was supported by the Spanish Ministerio de Ciencia e Innovacion (MICINN) grants BFU2009-06993 (S. F. E.) and BIO2006-13107 (C. L.) and by Generalitat Valenciana grant PROMETEO2010/016 (S. F. E.). G. R. is supported by a graduate fellowship from the Generalitat Valenciana (BFPI2007-160) and J.C. by a contract from MICINN grant TIN2006-12860. 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