The rockefeller university

Peripheral nerve function depends on a regulated process of axon and Schwann cell development. Schwann cells interact with peripheral neurons to sort and ensheath individual axons. Ablation of laminin gamma 1 in the peripheral nervous system (PNS) arrests Schwann cell development prior to radial sorting of axons. Peripheral nerves of laminin-deficient animals are disorganized and hypomyelinated. In this study, sciatic nerves of laminin-deficient mice were treated with syngenic murine adipose-derived stem cells (ADSCs). ADSCs expressed laminin in vitro and in vivo following transplant into mutant sciatic nerves. ADSC-treatment of mutant nerves caused endogenous Schwann cells to differentiate past the point of developmental arrest to sort and myelinate axons. This was shown by (1) functional, (2) ultrastructural, and (3) immunohistochemical analysis. Treatment of laminin-deficient nerves with either soluble laminin or the immortalized laminin-expressing cell line 3T3/L1 did not overcome endogenous Schwann cell developmental arrest. In summary, these results indicate that (1) laminin-deficient Schwann cells can be rescued, (2) a cell-based approach is beneficial in comparison with soluble protein treatment, and (3) mesenchymal stem cells modify sciatic nerve function via trophic effects rather than trans-differentiation in this system. (C) 2010 Wiley-Liss, Inc.

Purpose of review Immunoglobulin G (IgG) antibodies are centrally involved in pathogen clearance, tissue destruction and inflammation during autoimmune diseases, and have emerged as an important mediator of chronic organ rejection. Besides these pro-inflammatory activities, IgG antibodies can also have anti-inflammatory activities and are used to treat autoimmune disease and to prevent organ rejection in the form of high-dose intravenous immunoglobulin (IVIg) therapy. This review summarizes the mechanisms involved in these diverse activities of IgG. Recent findings Recent studies have highlighted the role of cellular receptors recognizing the antibody constant fragment (Fc gamma-receptors, Fc gamma R) for mediating IgG-dependent effector functions. In addition, the IgG-attached sugar moiety was identified as a molecular switch shifting IgG activity from a pro-inflammatory to an anti-inflammatory pathway. Besides the family of canonical Fc gamma Rs, specific Icam-3 grabbing nonintegrin-related 1 (SIGN-R1) and DC-SIGN were identified to recognize IgG glycoforms rich in sialic acid. Summary The identification of the IgG-attached sugar moiety as an important modulator of IgG activity makes it an attractive target to selectively potentiate either the pro-inflammatory or the anti-inflammatory activities of IgG. This finding will provide optimized IgG-based therapeutics to either enhance IgG-dependent tumor cell destruction or suppress IgG-dependent autoimmunity and organ rejection.

Background. It is unknown whether sex and race influence clinical outcomes following primary human immunodeficiency virus type 1 (HIV-1) infection. Methods. Data were evaluated from an observational, multicenter, primarily North American cohort of HIV-1 seroconverters. Results. Of 2277 seroconverters, 5.4% were women. At enrollment, women averaged .40 log(10) fewer copies/mL of HIV-1 RNA (P < .001) and 66 more CD4(+) T cells/mu L (P = .006) than men, controlling for age and race. Antiretroviral therapy (ART) was less likely to be initiated at any time point by nonwhite women and men compared to white men (P < .005), and by individuals from the southern United States compared to others (P = .047). Sex and race did not affect responses to ART after 6 months (P > .73). Women were 2.17-fold more likely than men to experience > 1 HIV/AIDS-related event (P < .001). Nonwhite women were most likely to experience an HIV/AIDS-related event compared to all others (P = .035), after adjusting for intravenous drug use and ART. Eight years after diagnosis, > 1 HIV/AIDS-related event had occurred in 78% of nonwhites and 37% of whites from the southern United States, and 24% of whites and 17% of nonwhites from other regions (P < .001). Conclusions. Despite more favorable clinical parameters initially, female HIV-1-seroconverters had worse outcomes than did male seroconverters. Elevated morbidity was associated with being nonwhite and residing in the southern United States.

The inherent instability of heptahelical G protein-coupled receptors (GPCRs) during purification and reconstitution is a primary impediment to biophysical studies and to obtaining high-resolution crystal structures. New approaches to stabilizing receptors during purification and screening reconstitution procedures are needed. Here we report the development of a novel homogeneous time-resolved fluorescence assay (HTRF) to quantify properly folded CC-chemokine receptor 5 (CCR5). The assay permits high-throughput thermal stability measurements of femtomole quantities of CCR5 in detergent and in engineered nanoscale apolipoprotein-bound bilayer (NABB) particles. We show that recombinantly expressed CCR5 can be incorporated into NABB particles in high yield, resulting in greater thermal stability compared with that of CCR5 in a detergent solution. We also demonstrate that binding of CCR5 to the HIV-1 cellular entry inhibitors maraviroc, AD101, CMPD 167, and vicriviroc dramatically increases receptor stability. The HTRF assay technology reported here is applicable to other membrane proteins and could greatly facilitate structural studies of GPCRs.

Histone H3K4 methylation is associated with active genes and, along with H3K27 methylation, is part of a bivalent chromatin mark that typifies poised developmental genes in embryonic stem cells (ESCs). However, its functional roles in ESC maintenance and differentiation are not established. Here we show that mammalian Dpy-30, a core subunit of the SET1/MLL histone methyltransferase complexes, modulates H3K4 methylation in vitro, and directly regulates chromosomal H3K4 trimethylation (H3K4me3) throughout the mammalian genome. Depletion of Dpy-30 does not affect ESC self-renewal, but significantly alters the differentiation potential of ESCs, particularly along the neural lineage. The differentiation defect is accompanied by defects in gene induction and in H3K4 methylation at key developmental loci. Our results strongly indicate an essential functional role for Dpy-30 and SET1/MLL complex-mediated H3K4 methylation, as a component of the bivalent mark, at developmental genes during the ESC fate transitions.

The collection of a large number of B-hadron decays to hadronic final states at the CDF II Detector is possible due to the presence of a trigger that selects events based on track impact parameters. However, the nature of the selection requirements of the trigger introduces a large bias in the observed proper-decay-time distribution. A lifetime measurement must correct for this bias, and the conventional approach has been to use a Monte Carlo simulation. The leading sources of systematic uncertainty in the conventional approach are due to differences between the data and the Monte Carlo simulation. In this paper, we present an analytic method for bias correction without using simulation, thereby removing any uncertainty due to the differences between data and simulation. This method is presented in the form of a measurement of the lifetime of the B- using the mode B- -> D-0 pi(-). The B- lifetime is measured as tau(-)(B) = 1.663 +/- 0.023 +/- 0.015 ps, where the first uncertainty is statistical and the second systematic. This new method results in a smaller systematic uncertainty in comparison to methods that use simulation to correct for the trigger bias.

We investigate a model for the dynamics of a solid object, which moves over a randomly vibrating solid surface and is subject to a constant external force. The dry friction between the two solids is modelled phenomenologically as being proportional to the sign of the object's velocity relative to the surface, and therefore shows a discontinuity at zero velocity. Using a path integral approach, we derive analytical expressions for the transition probability of the object's velocity and the stationary distribution of the work done on the object due to the external force. From the latter distribution, we also derive a fluctuation relation for the mechanical work fluctuations, which incorporates the effect of the dry friction.

Blood pressure (BP) assessment may be vulnerable to bias by increased BP variability. Uncertainty in determining BP control is inherent to the clinic setting. We analyzed a registry of 3949 patients referred for ambulatory BP monitoring. The difference between clinic and ambulatory readings was plotted against ambulatory BP variability, assessed by standard deviation. In addition, BP variability of patients with clinic and awake ambulatory hypertension was compared with that of patients with controlled BP and sustained hypertension, respectively. The average clinic-ambulatory systolic BP difference was 5 +/- 17/3 +/- 9 mm Hg. Patients with >10-mm Hg systolic difference had higher systolic ambulatory BP standard deviation (14.9 +/- 4.2 mm Hg) compared to patients with a difference of 0 to 10-mm Hg (standard deviation 12.5 +/- 3.7 mm Hg). Patients with masking (negative clinic-ambulatory BP difference) also had comparatively higher standard deviation (14.4 +/- 4.9 mm Hg P<0.0001). Greater ambulatory BP variability carried increased risk for both false diagnosis of hypertension (odds ratio (OR): 2.09, 95% confidence interval (CI): 1.58-2.76), and missed clinic diagnosis of hypertension (OR: 1.86, 95% confidence interval: 1.48-2.33). The former was more striking in women, in whom high variability carried greater odds for false diagnosis of hypertension (OR: 2.76, 95% confidence interval: 1.96-3.89). Thus, clinic misjudgment of BP control may stem in part from high BP variability. Women with high BP variability are more susceptible to hypertension misdiagnosis. It is possible that high BP variability contributes to the increased cardiovascular risk related to both masked hypertension and white coat hypertension. Hypertension Research (2011) 34, 187-192; doi: 10.1038/hr.2010.190; published online 11 November 2010

Numerous studies indicate that Sirtuin 1 (SIRT1), a mammalian nicotinamide adenine dinucleotide (NAD(+))-dependent histone deacetylase (HDAC), plays a crucial role in p53-mediated stress responses by deacetylating p53. Nevertheless, the acetylation levels of p53 are dramatically increased upon DNA damage, and it is not well understood how the SIRT1-p53 interaction is regulated during the stress responses. Here, we identified Set7/9 as a unique regulator of SIRT1. SIRT1 interacts with Set7/9 both in vitro and in vivo. In response to DNA damage in human cells, the interaction between Set7/9 and SIRT1 is significantly enhanced and coincident with an increase in p53 acetylation levels. Importantly, the interaction of SIRT1 and p53 is strongly suppressed in the presence of Set7/9. Consequently, SIRT1-mediated deacetylation of p53 is abrogated by Set7/9, and p53-mediated transactivation is increased during the DNA damage response. Of note, whereas SIRT1 can be methylated at multiple sites within its N terminus by Set7/9, a methylation-defective mutant of SIRT1 still retains its ability to inhibit p53 activity. Taken together, our results reveal that Set7/9 is a critical regulator of the SIRT1-p53 interaction and suggest that Set7/9 can modulate p53 function indirectly in addition to acting through a methylation-dependent mechanism.