The rockefeller university

The cytokine IFN-alpha is secreted during viral infections and has been shown to inhibit telomerase activity and accelerate T cell differentiation in vivo. However, the mechanism for this inhibition is not clear. In this study, we show that IFN-alpha inhibits both the transcription and translation of human telomerase reverse transcriptase (hTERT), the catalytic component of telomerase, in activated CD8(+) T cells. This was associated with increased activity of the repressor of hTERT transcription E2 transcription factor and decreased activation of NF-kappa B that promotes hTERT transcription. However IFN-alpha did not affect the translocation of hTERT from the cytoplasm to the nucleus. IFN-alpha also inhibits AKT kinase activation but increases p38 MAPK activity, and both of these events have been shown previously to inhibit telomerase activity. Addition of BIRB796, an inhibitor of p38 activity, to IFN-alpha-treated cells reversed, in part, the inhibition of telomerase by this cytokine. Therefore, IFN-alpha can inhibit the enzyme telomerase in CD8(+) T cells by transcriptional and posttranslational mechanisms. Furthermore, the addition of IFN-alpha to CD8(+)CD27(+)CD28(+) T cells accelerates the loss of both these costimulatory molecules. This suggests that persistent viral infections may contribute to the accumulation of highly differentiated/senescent CD8(+)CD27(-)CD28(-) T cells during aging by promoting IFN-alpha secretion during repeated episodes of viral reactivation.

Staphylococcus aureus is a gram-positive cocci and an important human commensal bacteria and pathogen. S. aureus infections are increasingly difficult to treat because of the emergence of highly resistant MRSA (methicillin-resistant S. aureus) strains. Here we present a method to study differential gene expression in S. aureus using high-throughput RNA-sequencing (RNA-seq). We used RNA-seq to examine gene expression in S. aureus RN4220 cells containing an exogenously expressed transcription factor and between two S. aureus strains (RN4220 and NCTC8325-4). We investigated the sequence and gene expression differences between RN4220 and NCTC8325-4 and used the RNA-seq data to identify S. aureus promoters suitable for in vitro analysis. We used RNA-seq to describe, on a genome wide scale, genes positively and negatively regulated by the phage encoded transcription factor gp67. RNA-seq offers the ability to study differential gene expression with single-nucleotide resolution, and is a considerable improvement over the predominant genome-wide transcriptome technologies used in S. aureus.

One of the earliest steps in embryonic development is the specification of the germ layers, the subdivision of the blastula embryo into endoderm, mesoderm and ectoderm. Maternally expressed members of the Transforming Growth Factor beta(TGF beta) family influence all three germ layers; the ligands are required to induce endoderm and mesoderm, whereas inhibitors are required for formation of the ectoderm. Here, we demonstrate a vital role for maternal Coco, a secreted antagonist of TGF beta signalling, in this process. We show that Coco is required to prevent Activin and Nodal signals in the dorsal marginal side of the embryo from invading the prospective ectoderm, thereby restricting endoderm-and mesoderm-inducing signals to the vegetal and marginal zones of the pregastrula Xenopus laevis embryo.

The visual system uses continuity as a cue for grouping oriented line segments that define object boundaries in complex visual scenes. Many studies support the idea that long-range intrinsic horizontal connections in early visual cortex contribute to this grouping. Top-down influences in primary visual cortex (V1) play an important role in the processes of contour integration and perceptual saliency, with contour-related responses being task dependent. This suggests an interaction between recurrent inputs to V1 and intrinsic connections within V1 that enables V1 neurons to respond differently under different conditions. We created a network model that simulates parametrically the control of local gain by hypothetical top-down modification of local recurrence. These local gain changes, as a consequence of network dynamics in our model, enable modulation of contextual interactions in a task-dependent manner. Our model displays contour-related facilitation of neuronal responses and differential foreground vs. background responses over the neuronal ensemble, accounting for the perceptual pop-out of salient contours. It quantitatively reproduces the results of single-unit recording experiments in V1, highlighting salient contours and replicating the time course of contextual influences. We show by means of phase-plane analysis that the model operates stably even in the presence of large inputs. Our model shows how a simple form of top-down modulation of the effective connectivity of intrinsic cortical connections among biophysically realistic neurons can account for some of the response changes seen in perceptual learning and task switching.

The cytosolic pathogen sensor RIG-I is activated by RNAs with exposed 5'-triphosphate (5'-ppp) and terminal double-stranded structures, such as those that are generated during viral infection. RIG-I has been shown to translocate on dsRNA in an ATP-dependent manner. However, the precise role of the ATPase activity in RIG-I activation remains unclear. Using in vitro-transcribed Sendai virus defective interfering RNA as a model ligand, we show that RIG-I oligomerizes on 5'-ppp dsRNA in an ATP hydrolysis-dependent and dsRNA length-dependent manner, which correlates with the strength of type-I interferon (IFN-I) activation. These results establish a clear role for the ligand-induced ATPase activity of RIG-I in the stimulation of the IFN response.

Taylor's law (TL), a widely verified empirical relationship in ecology, states that the variance of population density is approximately a power-law function of mean density. The growth-rate theorem (GR) states that, in a subdivided population, the rate of change of the overall growth rate is proportional to the variance of the subpopulations' growth rates. We show that continuous-time exponential change implies GR at every time and, asymptotically for large time, TL with power-law exponent 2. We also show why diverse population-dynamic models predict TL in the limit of large time by identifying simple features these models share: If the mean population density and the variance of population density are (exactly or asymptotically) non-constant exponential functions of a parameter (e.g., time), then the variance of density is (exactly or asymptotically) a power-law function of mean density. (C) 2013 Elsevier Inc. All rights reserved.

1. The power-law dependence of metabolic rate on body mass has major implications at every level of ecological organization. However, the overwhelming majority of studies examining this relationship have used basal or resting metabolic rates, and/or have used data consisting of species-averaged masses and metabolic rates. Field metabolic rates are more ecologically relevant and are probably more directly subject to natural selection than basal rates. Individual rates might be more important than species-average rates in determining the outcome of ecological interactions, and hence selection. 2. We here provide the first comprehensive database of published field metabolic rates and body masses of individual birds and mammals, containing measurements of 1498 animals of 133 species in 28 orders. We used linear mixed-effects models to answer questions about the body mass scaling of metabolic rate and its taxonomic universality/heterogeneity that have become classic areas of controversy. Our statistical approach allows mean scaling exponents and taxonomic heterogeneity in scaling to be analysed in a unified way while simultaneously accounting for nonindependence in the data due to shared evolutionary history of related species. 3. The mean power-law scaling exponents of metabolic rate vs. body mass relationships were 0.71 [95% confidence intervals (CI) 0.625-0.795] for birds and 0.64 (95% CI 0.564-0.716) for mammals. However, these central tendencies obscured meaningful taxonomic heterogeneity in scaling exponents. The primary taxonomic level at which heterogeneity occurred was the order level. Substantial heterogeneity also occurred at the species level, a fact that cannot be revealed by species-averaged data sets used in prior work. Variability in scaling exponents at both order and species levels was comparable to or exceeded the differences 3/4-2/3 = 1/12 and 0.71-0.64. 4. Results are interpreted in the light of a variety of existing theories. In particular, results are consistent with the heat dissipation theory of Speakman & Krol (2010) and provided some support for the metabolic levels boundary hypothesis of Glazier (2010). 5. Our analysis provides the first comprehensive empirical analysis of the scaling relationship between field metabolic rate and body mass in individual birds and mammals. Our data set is a valuable contribution to those interested in theories of the allometry of metabolic rates.

The initiation of the first methadone maintenance treatment program (MMT) in Macao was founded in collaboration between MMT clinics in the USA and Israel. All patients admitted into treatment between October 2005 and October 2008 were prospectively followed through March 2010. Of the 163 patients, 81% were male, the mean age on admission was 39.5 (sd = 10.2). Seventy-three percent (n = 119) were hepatitis C sera positive, and 4.9% (n = 8) were HIV sera positive. One-year treatment retention rate was 59.5%, with 52.6% of the 95 patients who stayed in treatment having an opiate-negative urine test at the 10-month evaluation. Four and a half years of follow-up showed mean long-term retention (Kaplan Meier analyses) of 2.2 years. Higher methadone dose (>= 80mg/day) and hepatitis C sera positive status were predictors for longer treatment retention. This study describes an effective model of MMT that supports the expansion of addiction treatment in other countries.

Measurements are presented of the production of primary K-S(0) and Lambda particles in proton-proton collisions at root s = 7 TeV in the region transverse to the leading charged-particle jet in each event. The average multiplicity and average scalar transverse momentum sum of K-S(0) and Lambda particles measured at pseudorapidities vertical bar eta vertical bar < 2 rise with increasing charged-particle jet p(T) in the range 1-10 GeV/c and saturate in the region 10-50 GeV/c. The rise and saturation of the strange-particle yields and transverse momentum sums in the underlying event are similar to those observed for inclusive charged particles, which confirms the impact-parameter picture of multiple parton interactions. The results are compared to recent tunes of the PYTHIA Monte Carlo event generator. The PYTHIA simulations underestimate the data by 15%-30% for K-S(0) mesons and by about 50% for Lambda baryons, a deficit similar to that observed for the inclusive strange-particle production in non-single-diffractive proton-proton collisions. The constant strange-to charged-particle activity ratios with respect to the leading jet p(T) and similar trends for mesons and baryons indicate that the multiparton-interaction dynamics is decoupled from parton hadronization, which occurs at a later stage.

Dendritic cells (DCs), monocytes, and macrophages are closely related phagocytes that share many phenotypic features and, in some cases, a common developmental origin. Although the requirement for DCs in initiating adaptive immune responses is well appreciated, the role of monocytes and macrophages remains largely undefined, in part because of the lack of genetic tools enabling their specific depletion. Here, we describe a two-gene approach that requires overlapping expression of LysM and Csf1r to define and deplete monocytes and macrophages. The role of monocytes and macrophages in immunity to pathogens was tested by their selective depletion during infection with Citrobacter rodentium. Although neither cell type was required to initiate immunity, monocytes and macrophages contributed to the adaptive immune response by secreting IL-12, which induced Th1 polarization and IFN-gamma secretion. Thus, whereas DCs are indispensable for priming naive CD4(+) T cells, monocytes and macrophages participate in intestinal immunity by producing mediators that direct T cell polarization.