The rockefeller university

Ganoderma lucidum (G. lucidum) is a medicinal mushroom long used in Asia as a folk remedy to promote health and longevity. Recent studies indicate that G. lucidum activates NK cells, but the molecular mechanism underlying this effect has not been studied so far. To address this question, we prepared a water extract of G. lucidum and examined its effect on NK cells. We observed that G. lucidum treatment increases NK cell cytotoxicity by stimulating secretion of perforin and granulysin. The mechanism of activation involves an increased expression of NKG2D and natural cytotoxicity receptors (NCRs), as well as increased phosphorylation of intracellular MAPKs. Our results indicate that G. lucidum induces NK cell cytotoxicity against various cancer cell lines by activating NKG2D/NCR receptors and MAPK signaling pathways, which together culminate in exocytosis of perforin and granulysin. These observations provide a cellular and molecular mechanism to account for the reported anticancer effects of G. lucidum extracts in humans.

We use ideas from kinetic proofreading, an error-correcting mechanism in biology, to identify new kinetic regimes in nonequilibrium systems. These regimes are defined by the sensitivity of the occupancy of a state of the system to a change in its energy. In biological contexts, higher sensitivity corresponds to stronger discrimination between molecular substrates with different energetics competing in the same reaction. We study this discriminatory ability in systems with discrete states that are connected by a general network of transitions. We find multiple regimes of different discriminatory ability when the energy of a given state of the network is varied. Interestingly, the occupancy of the state can even increase with its energy, corresponding to an "antiproofreading" regime. The number and properties of such discriminatory regimes are limited by the topology of the network. Finally, we find that discriminatory regimes can be changed without modifying any "hard-wired" structural aspects of the system but rather by simply changing external chemical potentials.

Toll-like receptors (TLRs) play an important role in immunity and mediate their actions via multiple signaling pathways, in particular, the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kappa B) pathway. Rare inherited defects of TLR- and NF-kappa B-dependent responses have recently been recognized. These primary immunodeficiencies predispose children to life-threatening infections and often remain undiagnosed. Establishing a sensitive, specific, cost-effective and simple method for diagnosis is therefore important. In this article, we review the known defects of TLR- and NF-kappa B-mediated pathways and the assays that can be used to screen for such defects.

Background: IL-23 expression is increased in psoriatic lesions and might regulate T(H)17 T-cell counts in patients with psoriasis. Objectives: We sought to test a novel IL-23-specific therapeutic agent for the treatment of psoriasis. Methods: In this randomized, double-blind, placebo-controlled study the safety, tolerability, and clinical response of guselkumab, an anti-IL-23-specific mAb, were evaluated in patients with moderate-to-severe plaque psoriasis. A total of 24 patients were randomized to receive a single dose of placebo or 10, 30, 100, or 300 mg of guselkumab. Clinical response was assessed by using the Psoriasis Area and Severity Index (PASI). Additionally, histologic analysis and gene expression in skin biopsy specimens from guselkumab-treated patients were compared with those from placebo-treated patients. Results: At week 12, 50% (10 mg), 60% (30 and 100 mg), and 100% (300 mg) of guselkumab-treated patients, respectively, achieved a 75% improvement in PASI scores from baseline compared with 0% of placebo-treated patients. Improvements in PASI scores were generally maintained through week 24 in all guselkumab-treated patients. The proportion of patients experiencing an adverse event was comparable between the combined guselkumab (13/20 [65.0%]) and placebo (2/4 [50.0%]) groups through week 24. Analysis of lesional and nonlesional skin biopsy specimens demonstrated decreases in epidermal thickness and T-cell and dendritic cell expression in guselkumab-treated patients compared with values seen in placebo-treated patients. At week 12, significant reductions in psoriasis gene expression and serum IL-17A levels were observed in guselkumab-treated patients. Conclusion: IL-23 inhibition with a single dose of guselkumab results in clinical responses in patients with moderate-to-severe psoriasis, suggesting that neutralization of IL-23 alone is a promising therapy for psoriasis.

A search for baryon number violation (BNV) in top-quark decays is performed using pp collisions produced by the LHC at root s = 8 TeV. The top-quark decay considered in this search results in one light lepton (muon or electron), two jets, but no neutrino in the final state. Data used for the analysis were collected by the CMS detector and correspond to an integrated luminosity of 19.5 fb(-1). The event selection is optimized for top quarks produced in pairs, with one undergoing the BNV decay and the other the standard model hadronic decay to three jets. No significant excess of events over the expected yield from standard model processes is observed. The upper limits at 95% confidence level on the branching fraction of the BNV top-quark decay are calculated to be 0.0016 and 0.0017 for the muon and the electron channels, respectively. Assuming lepton universality, an upper limit of 0.0015 results from the combination of the two channels. These limits are the first that have been obtained on a BNV process involving the top quark. (C) 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license

We have reported previously that autophagy is responsible for amyloid precursor protein-C-terminal fragment (APP-CTF) degradation and therefore A clearance. To elucidate the underlying mechanism, using LC3 affinity purification and mass spectrometry analysis, immunoprecipitation (IP), as well as live imaging analysis, we identified and demonstrated that the adaptor-related protein complex 2 (AP2) and PICALM (phosphatidylinositol binding clathrin assembly protein) are in a complex with LC3 and APP-CTF. Taken together, this new set of data suggests that the AP2-PICALM complex functions as an autophagic cargo receptor for the recognition and shipment of APP-CTF from the endocytic pathway to the LC3-dependent autophagic degradation pathway. Interestingly this AP2-LC3 connection seems to be involved in chemically-induced APP-CTF clearance as we observed using the small compound SMER28. The effect observed following SMER28 was significantly reduced after silencing AP2. While more work is required to elucidate the detailed molecular mechanisms involved, our actual data suggest that there is some level of specificity in the steps mentioned above.

Coagulase-negative staphylococci (CoNS) are believed to function as reservoirs, as well as possible sources of staphylococcal chromosome cassette mec (SCCmec) to Staphylococcus aureus, but the frequency, preferred partners, and factors promoting SCCmec transfer are not known. Such postulated in vivo genetic transfer events are likely to occur at anatomical sites such as the normal nasal mucosa, which is known to be colonized by both CoNS and coagulase positive staphylococci. In this study, we characterized S. aureus and CoNS strains colonizing the anterior nares of 67 patients in Denmark. A total of 54 patients (80%) were colonized with staphylococci that included nine different species identified by internal transcribed spacer PCR (ITS-PCR) and 16S RNA sequencing. The highest rates of colonization were found for S. epidermidis (58%) and S. aureus (39%). Methicillin resistance was present in S. aureus (53%), S. epidermidis (53%), S. haemolyticus (33%), and S. hominis (62%). Genetic backgrounds were characterized by spa typing for S. aureus and by pulsed-field gel electrophoresis for CoNS. SCCmec typing showed that SCCmec type IV (2B) was the most common in the entire collection (65%). Carriage of multiple species was detected in 20 patients (30%), 16 of whom were colonized with both S. aureus and S. epidermidis. In two cases, simultaneous carriage of different methicillin resistant species was detected. However, the strains carried different SCCmec types. Additional studies in the same epidemiological settings are warranted to identify interspecific genetic events that involve the acquisition of SCCmec by S. aureus.

Early life experiences are thought to have long-lasting effects on cognitive, emotional, and social function during adulthood. Changes in neuroendocrine function, particularly the hypothalamic-pituitary-adrenal (HPA) axis, contribute to these systems-level behavioral effects. In searching for causal mechanisms underlying these early experience effects, pioneering research has demonstrated an important role for maternal care in offspring development, and this has led to two persistent ideas that permeate current research and thinking: first, environmental impact on the developing infant is mediated through maternal care behavior; second, the more care that a mother provides, the better off her offspring. While a good beginning, the reality is likely more complex. In this review, we critically examine these ideas and propose a computationally-motivated theoretical framework, and within this framework, we consider evidence supporting a hypothesis of maternal modulation. These findings may inform policy decisions in the context of child health and development. (C) 2013 Elsevier Inc. All rights reserved.

CLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p. R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pretRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis, and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis.