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The results of the first search for long-lived gluinos produced in 7 TeV pp collisions at the CERN Large Hadron Collider are presented. The search looks for evidence of long-lived particles that stop in the CMS detector and decay in the quiescent periods between beam crossings. In a dataset with a peak instantaneous luminosity of 1 x 10(32) cm(-2) s(-1), an integrated luminosity of 10 pb(-1), and a search interval corresponding to 62 hours of LHC operation, no significant excess above background was observed. Limits at the 95% confidence level on gluino pair production over 13 orders of magnitude of gluino lifetime are set. For a mass difference m((g) over tilde) - m((chi) over tilde1)(0) >100 GeV/c(2), and assuming BR((g) over tilde -> g<(chi over bar>(0)(1)) = 100%, m((g) over tilde) < 370 GeV/c(2) are excluded for lifetimes from 10 mu s to 1000 s.

Simulation of genotypes in pedigrees is an important tool to evaluate the power of a linkage or an association study and to assess the empirical significance of results. SLINK is a widely-used package for pedigree simulations, but its implementation has not previously been described in a published paper. SLINK was initially derived from the LINKAGE programs. Over the 20 years since its release, SLINK has been modified to incorporate faster algorithms, notably from the linkage analysis package FASTLINK, also derived from LINKAGE. While SLINK can simulate genotypes on pedigrees of high complexity, one limitation of SLINK, as with most methods based on peeling algorithms to evaluate pedigree likelihoods, is the small number of linked markers that can be generated. The software package SUP includes an elegant wrapper for SLINK that circumvents the limitation on number of markers by using descent markers generated by SLINK to simulate a much larger number of markers on the same chromosome, linked and possibly associated with a trait locus. We have released new coordinated versions of SLINK (3.0; available from http://watson.hgen.pitt.edu) and SUP (v090804; available from http://mlemire.freeshell.org/software or http://watson.hgen.pitt.edu) that integrate the two software packages. Thereby, we have removed some of the previous limitations on the joint functionality of the programs, such as the number of founders in a pedigree. We review the history of SLINK and describe how SLINK and SUP are now coordinated to permit the simulation of large numbers of markers linked and possibly associated with a trait in large pedigrees. Copyright (C) 2011 S. Karger AG, Basel

IFN-gamma has been used in the treatment of IL-12R beta 1 deficiency patients with disseminated BCG infection (BCGosis), but the optimal dose to reach efficacy is not clear. We used IFN-gamma in the treatment of a 2.7-year-old patient with IL-12R beta 1 deficiency and refractory BCG-osis. IFN gamma was started at a dose of 50 mu g/m(2) 3 times per week. The dose was upgraded to 100 mcg/m(2) after 3 months, then to 200 mcg/m(2) 6 months afterwards. Serum mycobactericidal activity and lymphocytes number and function were evaluated throughout the study. There was no clinical response to IFN-gamma with 50 or 100 mu g/m2 doses. However, there was some response to the 200 mu g/m(2) dose with no additional adverse effects. The serum mycobactericidal activity was not significantly different during the whole treatment period. Lymphocytes proliferation in response to PHA was significantly higher after 3 months of using the highest dose as compared to the lowest dose. The tuberculin skin test reaction remained persistently negative. We conclude that in a patient with IL-12R beta 1 deficiency, IFN-gamma at a dose of 200 mu g/m(2), but not at lower dosages, was found to have a noticeable clinical effect with no additional adverse effects.

Antibody maturation requires class switch recombination (CSR) and somatic hypermutation (SHM), both of which are initiated by activation-induced cytidine deaminase (AID). AID deaminates cytosine residues resulting in mismatches that are differentially processed to produce double-strand breaks in Ig switch (5) regions that lead to CSR, or to point mutations in variable (V) exons resulting in SHM. Although AID was first thought to be I8-specific, recent work indicates that it also targets a diverse group of non-Ig loci, including genes such as Bcl6 and c-myc, whose modification by AID results in lymphoma-associated mutations and translocations. Here, we review the recent literature on AID targeting and the role for transcriptional stalling in recruitment of this enzyme to Ig and non-Ig loci. We propose a model for AID recruitment based on transcriptional stalling, which reconciles several of the key features of SHM, CSR, and lymphoma-associated translocation.

The paraneoplastic neurologic diseases are a set of brain degenerations that develop in the setting of occult cancer. These disorders arise when common cancers express brain proteins, triggering an anti-tumor immune response and tumor immunity. Studies of the nature of these brain-cancer proteins has revealed a new world of neuron-specific RNA binding proteins whose functions may be co-opted by tumor cells. The interest in their function has spawned the development of new methods and strategies to understand RNA-protein regulation in living tissues. These approaches, and the new biology they reveal, are discussed here.

The brain is the key organ of stress processes. It determines what individuals will experience as stressful, it orchestrates how individuals will cope with stressful experiences, and it changes both functionally and structurally as a result of stressful experiences. Within the brain, a distributed, dynamic, and plastic neural circuitry coordinates, monitors, and calibrates behavioral and physiological stress response systems to meet the demands imposed by particular stressors. These allodynamic processes can be adaptive in the short term (allostasis) and maladaptive in the long term (allostatic load). Critically, these processes involve bidirectional signaling between the brain and body. Consequently, allostasis and allostatic load can jointly affect vulnerability to brain-dependent and stress-related mental and physical health conditions. This review focuses on the role of brain plasticity in adaptation to, and pathophysiology resulting from, stressful experiences. It also considers interventions to prevent and treat chronic and prevalent health conditions via allodynamic brain mechanisms.

Mass spectrometry (MS) is rapidly becoming an essential tool for biologists and biochemists in their efforts to throw light on molecular mechanisms within cellular systems. Used in unison with genome sequence data, MS has developed into the method of choice for identifying proteins, elucidating their posttranslational modifications, and reading out their functional interactions. Variations of the method have even begun to enable accurate mass determination of intact protein complexes, allowing for direct determination of subunit stoichiometry and the interactions between the subunits. Advances in mass spectrometric technologies have also led to great improvements in our ability to probe and define many of the other key molecular players in cells, including the all important lipid components. We provide here some perspectives on the explosion of applications of MS to protein science, systems biology, proteomics, lipidomics, and cell biology in general.

Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1 Rs) have TIR intracellular domains that engage two main signaling pathways, via the TIR-containing adaptors MyD88 (which is not used by TLR3) and TRIF (which is used only by TLR3 and TLR4). Extensive studies in inbred mice in various experimental settings have attributed key roles in immunity to TLR- and IL-1R-mediated responses, but what contribution do human TLRs and IL-1Rs actually make to host defense in the natural setting? Evolutionary genetic studies have shown that human intracellular TLRs have evolved under stronger purifying selection than surface-expressed TLRs, for which the frequency of missense and nonsense alleles is high in the general population. Epidemiological genetic studies have yet to provide convincing evidence of a major contribution of common variants of human TLRs, IL-1 Rs, or their adaptors to host defense. Clinical genetic studies have revealed that rare mutations affecting the TLR3-TRIF pathway underlie herpes simplex virus encephalitis, whereas mutations in the TIR-MyD88 pathway underlie pyogenic bacterial diseases in childhood. A careful reconsideration of the contributions of TLRs and IL-1 Rs to host defense in natura is required.

Multiple levels of control are in play to regulate pluripotency and differentiation in human embryonic stem cells (hESCs). At the transcriptional level, the core factors OCT4, NANOG and SOX2 form a positive autoregulatory loop that is pivotal for maintaining the undifferentiated state. At the post-transcriptional level, microRNAs (miRNAs) belonging to the miR-302 family are emerging as key players in the control of proliferation and cell fate determination during differentiation. Here, we show that the transcriptional factors OCT4 and NR2F2 (COUP-TFII) and the miRNA miR-302 are linked in a regulatory circuitry that critically regulate both pluripotency and differentiation in hESCs. In the undifferentiated state, both OCT4 and the OCT4-induced miR-302 directly repress NR2F2 at the transcriptional and post-transcriptional level, respectively. Conversely, NR2F2 directly inhibits OCT4 during differentiation, triggering a positive feedback loop for its own expression. In addition, we show that regulation of NR2F2 activity itself relies on alternative splicing and transcriptional start site choice to generate a full-length transcriptionally active isoform and shorter variants, which enhance the activity of the long isoform. During hESC differentiation, NR2F2 is first detected at the earliest steps of neural induction and thus is among the earliest human embryonic neural markers. Finally, our functional analysis points to a crucial role for NR2F2 in the activation of neural genes during early differentiation in humans. These findings introduce a new molecular player in the context of early embryonic stem cell state and cell fate determination in humans. The EMBO Journal (2011) 30, 237-248. doi:10.1038/emboj.2010.319; Published online 10 December 2010

Studies of retroviruses have been instrumental in revealing the existence of an array of antiviral proteins, or restriction factors, and the mechanisms by which they function. Some restriction factors appear to specifically inhibit retrovirus replication, while others have a broader antiviral action. Here, we briefly review current understanding of the mechanisms by which several such proteins exert antiviral activity. We also discuss how retroviruses have evolved to evade or antagonize antiviral proteins, including through the action of viral accessory proteins. Restriction factors, their viral targets and antagonists have exerted evolutionary pressure on each other, resulting in specialization and barriers to cross-species transmission. Potentially, this recently revealed intrinsic system of antiviral immunity might be mobilized for therapeutic benefit.