A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28-let-7 pathway

The pluripotency factor Lin28 blocks the expression of let-7 microRNAs (miRNAs) in undifferentiated cells during development and functions as an oncogene in a subset of cancers1. Lin28 binds to let-7 precursor RNAs and recruits 3′ terminal uridylyl transferases (TUTases) to selectively inhibit let-7 biogenesis2–4. Uridylated pre-let-7 is refractory to processing by Dicer and is rapidly degraded by an unknown ribonuclease5. Here we identify Dis3l2 as the 3′-5′ exonuclease responsible for the decay of uridylated pre-let-7. Biochemical reconstitution assays reveal that 3′ oligouridylation stimulates Dis3l2 activity in vitro, and knockdown of Dis3l2 in mouse embryonic stem cells leads to the stabilization of pre-let-7. Our study establishes 3′ oligouridylation as an RNA decay signal for Dis3l2 and identifies the first physiological RNA substrate of this novel exonuclease that is mutated in the Perlman syndrome of fetal overgrowth and predisposition to Wilms’ tumor6

Resolved Mid-IR Emission in the Narrow Line Region of NGC 4151

We present subarcsecond resolution mid infrared images of NGC 4151 at 10.8 micron and 18.2 micron. These images were taken with the University of Florida mid-IR camera/spectrometer OSCIR at the Gemini North 8-m telescope. We resolve emission at both 10.8 micron and 18.2 micron extending ~ 3.5" across at a P.A. of ~ 60 degrees. This coincides with the the narrow line region of NGC 4151 as observed in [OIII] by the Hubble Space Telescope. The most likely explanation for this extended mid-IR emission is dust in the narrow line region heated by a central engine. We find no extended emission associated with the proposed torus and place an upper limit on its mid-IR size of less than or equal to ~ 35 pc.Comment: accepted for publication in the Astrophysical Journal, 19 pages including 5 figure

The quadratic spinor Lagrangian is equivalent to the teleparallel theory

The quadratic spinor Lagrangian is shown to be equivalent to the teleparallel / tetrad representation of Einstein's theory. An important consequence is that the energy-momentum density obtained from this quadratic spinor Lagrangian is essentially the same as the ``tensor'' proposed by Moller in 1961.Comment: 10 pages, RevTe

The characteristics of cognitive neuroscience tests in a schizophrenia cognition clinical trial: Psychometric properties and correlations with standard measures.

In comparison to batteries of standard neuropsychological tests, cognitive neuroscience tests may offer a more specific assessment of discrete neurobiological processes that may be aberrant in schizophrenia. However, more information regarding psychometric properties and correlations with standard neuropsychological tests and functional measures is warranted to establish their validity as treatment outcome measures. The N-back and AX-Continuous Performance Task (AX-CPT) are two promising cognitive neuroscience tests designed to measure specific components of working memory and contextual processing respectively. In the current study, we report the psychometric properties of multiple outcome measures from these two tests as well as their correlations with standard neuropsychological measures and functional capacity measures. The results suggest that while the AX-CPT and N-back display favorable psychometric properties, they do not exhibit greater sensitivity or specificity with functional measures than standard neurocognitive tests

FcγRIIIa Expression on Monocytes in Rheumatoid Arthritis: Role in Immune-Complex Stimulated TNF Production and Non-Response to Methotrexate Therapy

OBJECTIVE:The expression of FcγRIIIa/CD16 may render monocytes targets for activation by IgG-containing immune complexes (IC). We investigated whether FcγRIIIa/CD16 was upregulated in rheumatoid arthritis (RA), associated with TNF production in response to IC-stimulation, and if this predicted response to methotrexate therapy. METHODS:FcγRIIIa/CD16 expression on CD14(low) and CD14++ monocytes was measured by flow cytometry in healthy controls and RA patients (early and long-standing disease). Intracellular TNF-staining was carried out after in vitro LPS or heat-aggregated immunoglobulin (HAG) activation. FcγRIIIa/CD16 expression pre- and post-steroid/methotrexate treatment was examined. RESULTS:Increased FcγRIIIa/CD16 expression on CD14++ monocytes in long-standing RA patients compared to controls was demonstrated (p = 0.002) with intermediate levels in early-RA patients. HAG-induced TNF-production in RA patients was correlated with the percentage of CD14++ monocytes expressing FcγRIIIa/CD16 (p<0.001). The percentage of CD14++ monocytes expressing FcγRIIIa/CD16 at baseline in early DMARD-naïve RA patients was negatively correlated with DAS28-ESR improvement 14-weeks post-methotrexate therapy (p = 0.003) and was significantly increased in EULAR non-responders compared to moderate (p = 0.01) or good responders (p = 0.003). FcγRIIIa/CD16 expression was not correlated with age, presence of systemic inflammation or autoantibody titers. CONCLUSION:Increased FcγRIIIa/CD16 expression on CD14++ monocytes in RA may result in a cell that has increased responsiveness to IC-stimulation. This monocyte subset may contribute to non-response to methotrexate therapy

Considering the impact of situation-specific motivations and constraints in the design of naturally ventilated and hybrid buildings

A simple logical model of the interaction between a building and its occupants is presented based on the principle that if free to do so, people will adjust their posture, clothing or available building controls (windows, blinds, doors, fans, and thermostats) with the aim of achieving or restoring comfort and reducing discomfort. These adjustments are related to building design in two ways: first the freedom to adjust depends on the availability and ease-of-use of control options; second the use of controls affects building comfort and energy performance. Hence it is essential that these interactions are considered in the design process. The model captures occupant use of controls in response to thermal stimuli (too warm, too cold etc.) and non-thermal stimuli (e.g. desire for fresh air). The situation-specific motivations and constraints on control use are represented through trigger temperatures at which control actions occur, motivations are included as negative constraints and incorporated into a single constraint value describing the specifics of each situation. The values of constraints are quantified for a range of existing buildings in Europe and Pakistan. The integration of the model within a design flow is proposed and the impact of different levels of constraints demonstrated. It is proposed that to minimise energy use and maximise comfort in naturally ventilated and hybrid buildings the designer should take the following steps: 1. Provide unconstrained low energy adaptive control options where possible, 2. Avoid problems with indoor air quality which provide motivations for excessive ventilation rates, 3. Incorporate situation-specific adaptive behaviour of occupants in design simulations, 4. Analyse the robustness of designs against variations in patterns of use and climate, and 5. Incorporate appropriate comfort standards into the operational building controls (e.g. BEMS)

Adolescent Report of Lifestyle Counseling

Background: Physician counseling on lifestyle factors has been recommended as one way to help combat the obesity epidemic in the United States. The aim of this study was to examine the frequency of lifestyle counseling among healthy weight, overweight, and obese adolescents and determine the contributions of adolescent weight and physical activity

No Evidence of XMRV or MuLV Sequences in Prostate Cancer, Diffuse Large B-Cell Lymphoma, or the UK Blood Donor Population

Xenotropic murine leukaemia virus-related virus (XMRV) is a recently described retrovirus which has been claimed to infect humans and cause associated pathology. Initially identified in the US in patients with prostate cancer and subsequently in patients with chronic fatigue syndrome, doubt now exists that XMRV is a human pathogen. We studied the prevalence of genetic sequences of XMRV and related MuLV sequences in human prostate cancer, from B cell lymphoma patients and from UK blood donors. Nucleic acid was extracted from fresh prostate tissue biopsies, formalin-fixed paraffin-embedded (FFPE) prostate tissue and FFPE B-cell lymphoma. The presence of XMRV-specific LTR or MuLV generic gag-like sequences was investigated by nested PCR. To control for mouse DNA contamination, a PCR that detected intracisternal A-type particle (IAP) sequences was included. In addition, DNA and RNA were extracted from whole blood taken from UK blood donors and screened for XMRV sequences by real-time PCR. XMRV or MuLV-like sequences were not amplified from tissue samples. Occasionally MuLV gag and XMRV-LTR sequences were amplified from Indian prostate cancer samples, but were always detected in conjunction with contaminating murine genomic DNA. We found no evidence of XMRV or MuLV infection in the UK blood donors