The rockefeller university

Apoptosis is a prominent metazoan cell death form. Yet, mutations in apoptosis regulators cause only minor defects in vertebrate development, suggesting that another developmental cell death mechanism exists. While some non-apoptotic programs have been molecularly characterized, none appear to control developmental cell culling. Linker-cell-type death (LCD) is a morphologically conserved non-apoptotic cell death process operating in Caenorhabditis elegans and vertebrate development, and is therefore a compelling candidate process complementing apoptosis. However, the details of LCD execution are not known. Here we delineate a molecular-genetic pathway governing LCD in C. elegans. Redundant activities of antagonistic Wnt signals, a temporal control pathway, and mitogen-activated protein kinase kinase signaling control heat shock factor 1 (HSF-1), a conserved stress-activated transcription factor. Rather than protecting cells, HSF-1 promotes their demise by activating components of the ubiquitin proteasome system, including the E2 ligase LET-70/UBE2D2 functioning with E3 components CUL-3, RBX-1, BTBD-2, and SIAH-1. Our studies uncover design similarities between LCD and developmental apoptosis, and provide testable predictions for analyzing LCD in vertebrates.

As improvements in neuroscience have enabled a better understanding of disorders of consciousness as well as methods to treat them, a hurdle that has become all too prevalent is the denial of coverage for treatment and rehabilitation services. In 2011, a settlement emerged from a Vermont District Court case, Jimmo v. Sebelius, which was brought to stop the use of an improvement standard that required tangible progress over an identifiable period of time for Medicare coverage of services. While the use of this standard can have deleterious effects on those with many chronic conditions, it is especially burdensome for those in the minimally conscious state (MCS), where improvements are unpredictable and often not manifested through repeatable overt behaviors. Though the focus of this paper is on the challenges of brain injury and the minimally conscious state, which an estimated 100,000 to 200,000 individuals suffer from in the United States, the post-Jimmo arguments presented can and should have a broad impact as envisioned by the plaintiffs who brought the case on behalf of multiple advocacy groups representing patients with a range of chronic care conditions.

A search for compositeness of electrons and muons is presented using a data sample of proton-proton collisions at a center-of-mass energy of root s = 8TeV collected with the CMS detector at the LHC and corresponding to an integrated luminosity of 19.7 fb(-1). Excited leptons (l*) produced via contact interactions in conjunction with a standard model lepton are considered, and a search is made for their gauge decay modes. The decays considered are l* -> l gamma and l* -> lZ , which give final states of two leptons and a photon or, depending on the Z-boson decay mode, four leptons or two leptons and two jets. The number of events observed in data is consistent with the standard model prediction. Exclusion limits are set on the excited lepton mass, and the compositeness scale Lambda. For the case M-l* = Lambda the existence of excited electrons (muons) is excluded up to masses of 2.45 (2.47) TeV at 95% confidence level. Neutral current decays of excited leptons are considered for the first time, and limits are extended to include the possibility that the weight factors f and f', which determine the couplings between standard model leptons and excited leptons via gauge mediated interactions, have opposite sign.

In Portugal, the 7-valent pneumococcal conjugate vaccine (PCV7) was not introduced in the national immunization plan but was commercially available between 2001 and 2010. We studied serotype distribution and antibiotic susceptibility of Streptococcus pneumoniae carried by children in 2009 and 2010. Vaccination with PCV7 was extracted from children's immunization bulletins and information on recent antimicrobial consumption was obtained through a questionnaire. For comparison, we included data from previous studies conducted since 1996: 1996-1999, 2001-2003,2006-2007. Pneumococci were isolated from nasopharyngeal samples of 1092 children up to six years old attending day-care in an urban area. Among these, 76% (819/1070) were vaccinated and 62% (677/1092) carried pneumococci. In 2009-2010, serotype replacement was extensive. Carriage of PCV7 serotypes was 4.9% and 5.8%, in 2009 and 2010, respectively, with the majority being of serotype 19F (carried by 4,3% and 4.6% of all participants, respectively). Colonization by serotype 19F was associated with vaccine status (7.7% (19/248) of non-vaccinees vs. 3.5% (29/818) of PCV7-vaccinees, p = 0.010). Carriage of serotype 19A was high in 2009 and 2010 (8.6% of all participants) consistent with values already observed in 2007; carriage of serotype 6A was <1% (10/1092), indicating a major decline after 2007 (5.8% or 31/538, p < 0.001). Non-vaccine serotypes increased and serotype 6C became the most frequently carried serotype in 2010 (11.2% (54/481)). High-level resistance to penicillin (MIC >= 2 mg/L) showed a decreasing trend (p < 0.001), whereas resistance to both penicillin and erythromycin increased (p <0,001) and was detected in 15-20% of all isolates in 2009-2010, most of which were non-vaccine serotypes. Antimicrobial use decreased over time (p < 0.001). In conclusion, widespread private use of PCV7 has impacted on colonization leading to near elimination of all PCV7 serotypes except for serotype 19F. Antimicrobial consumption declined but it may be too soon to observe generalized changes in antimicrobial resistance rates. (C) 2016 Elsevier Ltd. All rights reserved.

Here, we screened a 10,371 library of diverse molecules using a drug-sensitive fission yeast strain to identify compounds which cause defects in chromosome segregation during mitosis. We identified a phosphorium-ylide-based compound Cutin-1 which inhibits nuclear envelope expansion and nuclear elongation during the closed mitosis of fission yeast, and showed that its target is the a-subunit of fatty acid synthase. A point mutation in the dehydratase domain of Fas1 conferred in vivo and in vitro resistance to Cutin-1. Time-lapse photomicrography showed that the bulk of the chromosomes were only transiently separated during mitosis, and nucleoli separation was defective. Subsequently sister chromatids re-associated leading to chromosomal mis-segregation. These segregation defects were reduced when the nuclear volume was increased and were increased when the nuclear volume was reduced. We propose that there needs to be sufficient nuclear volume to allow the nuclear elongation necessary during a closed mitosis to take place for proper chromosome segregation, and that inhibition of fatty acid synthase compromises nuclear elongation and leads to defects in chromosomal segregation.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare inheritance syndrome, characterized by a disseminated infection with mycobacterium in children following BCG vaccination at birth. Regarding the vaccination program in Iran, it may consider as a public health problem. The pathogenesis of MSMD is dependent on either insufficient production of IFN-gamma (gamma) or inadequate response to it. Here, we want to introduce three cases including two siblings and one girl from two unrelated families with severe mycobacterial infections referred to Immunology, Asthma and Allergy Research Institute (IAARI), from 2013 to 2015; their MSMD was confirmed by both cytokine assessment and genetic analysis. Regarding the clinical features of the patients, cell proliferation against a mitogen and BCG antigen was ordered in a lymphocyte transformation test (LTT) setting. ELISA was performed for the measurement of IL-12p70 and IFN-gamma in whole blood samples activated by BCG + recombinant human IFN-gamma and BCG + recombinant human IL-12, respectively. In contrast to mitogen, the antigen-dependent proliferation activity of the patients' leukocytes was significantly lower than that in normal range. We identified a homozygous mutation in IL12RB1 gene for two kindred who had a homozygous mutation affecting an essential splice site. For the third patient, a novel frameshift deletion in IL12RB1 gene was found. The genetic study results confirmed the impaired function of stimulated lymphocytes to release IFN-gamma following stimulation with BCG+IL-12 while the response to rhIFN-gamma for IL-12p70 production was relatively intact. Our findings show that cellular and molecular assessments are needed for precise identification of immunodeficiency disorders especially those without clear-cut diagnostic criteria.

BackgroundThe endocannabinoid system has been found to play an important role in modulating alcohol intake. Inhibition or genetic deletion of fatty acid amide hydrolase (FAAH; a key catabolic enzyme for endocannabinoids) leads to increased alcohol consumption and preference in rodent models. A common human single-nucleotide polymorphism (SNP; C385A, rs324420) in the FAAH gene is associated with decreased enzymatic activity of FAAH, resulting in increased anandamide levels in both humans and FAAH C385A knock-in mice. MethodsAs this FAAH SNP has been reported to be associated with altered alcohol abuse, the present study used these genetic knock-in mice containing the human SNP C385A to determine the impact of variant FAAH gene on alcohol binge drinking in the drinking-in-the-dark (DID) model. ResultsWe found that the FAAH(A/A) mice had greater alcohol intake and preference than the wild-type FAAH(C/C) mice, suggesting that increased endocannabinoid signaling in FAAH(A/A) mice led to increased alcohol binge consumption. The specificity on alcohol vulnerability was suggested by the lack of any FAAH genotype difference on sucrose or saccharin intake. Using the binge DID model, we confirmed that selective CB1 receptor antagonist AM251 reduced alcohol intake in the wild-type mice. ConclusionsThese data suggest that there is direct and selective involvement of the human FAAH C385A SNP and CB1 receptors in alcohol binge drinking.

Social interactions make up to a large extent the prime material of episodic memories. We therefore asked how social signals are coded by neurons in the hippocampus. Human hippocampus is home to neurons representing familiar individuals in an abstract and invariant manner ( Quian Quiroga et al. 2009). In contradistinction, activity of rat hippocampal cells is only weakly altered by the presence of other rats ( von Heimendahl et al. 2012; Zynyuk et al. 2012). We probed the activity of monkey hippocampal neurons to faces and voices of familiar and unfamiliar individuals (monkeys and humans). Thirty-one percent of neurons recorded without prescreening responded to faces or to voices. Yet responses to faces were more informative about individuals than responses to voices and neuronal responses to facial and vocal identities were not correlated, indicating that in our sample identity information was not conveyed in an invariant manner like in human neurons. Overall, responses displayed by monkey hippocampal neurons were similar to the ones of neurons recorded simultaneously in inferotemporal cortex, whose role in face perception is established. These results demonstrate that the monkey hippocampus participates in the read-out of social information contrary to the rat hippocampus, but possibly lack an explicit conceptual coding of as found in humans.

We describe a measurement of the ratio of the cross sections times branching fractions of the B-c(+) meson in the decay mode B-c(+) -> J/psi mu(+)nu to the B+ meson in the decay mode B+ -> J/psi K+ in proton-antiproton collisions at center-of-mass energy root s = 1.96 TeV. The measurement is based on the complete CDF Run II data set, which comes from an integrated luminosity of 8.7 fb(-1). The ratio of the production cross sections times branching fractions for B-c(+) and B+ mesons with momentum transverse to the beam greater than 6 GeV/c and rapidity magnitude smaller than 0.6 is 0.211 +/- 0.012(stat)(-0.020)(+0.021)(syst). Using the known B+ -> J/psi K+ branching fraction, the known B+ production cross section, and a selection of the predicted B-c(+) -> J/psi mu(+nu) branching fractions, the range for the total B-c(+) production cross section is estimated.

Genetically encoded calcium indicators (GEC's) allow measurement of activity in large populations of neurons and in small neuronal compartments, over times of milliseconds to months. Although GFP-based GEC's are widely used for in vivo neurophysiology, GEC's with red-shifted excitation and emission spectra have advantages for in vivo imaging because of reduced scattering and absorption in tissue, and a consequent reduction in phototoxicity. However, current red GEC's are inferior to the state-of-the-art GFP-based GCaMP6 indicators for detecting and quantifying neural activity. Here we present improved red GEC's based on mRuby (jRCaMP1a, b) and mApple (jRGECO1a), with sensitivity comparable to GCaMP6. We characterized the performance of the new red GEC's in cultured neurons and in mouse, Drosophila, zebrafish and C. elegans in vivo. Red GEC's facilitate deep-tissue imaging, dual-color imaging together with GFP-based reporters, and the use of optogenetics in combination with calcium imaging.