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Recently discovered histone lysine acylation marks increase the functional diversity of nucleosomes well beyond acetylation. Here, we focus on histone butyrylation in the context of sperm cell differentiation. Specifically, we investigate the butyrylation of histone H4 lysine 5 and 8 at gene promoters where acetylation guides the binding of Brdt, a bromodomain-containing protein, thereby mediating stagespecific gene expression programs and post-meiotic chromatin reorganization. Genome-wide mapping data show that highly active Brdt-bound gene promoters systematically harbor competing histone acetylation and butyrylation marks at H4 K5 and H4 K8. Despite acting as a direct stimulator of transcription, histone butyrylation competes with acetylation, especially at H4 K5, to prevent Brdt binding. Additionally, H4 K5K8 butyrylation also marks retarded histone removal during late spermatogenesis. Hence, alternating H4 acetylation and butyrylation, while sustaining direct gene activation and dynamic bromodomain binding, could impact the final male epigenome features.

Aristolochic acid I (AM) existing in plant drugs from Aristolochia species is an environmental human carcinogen associated with urothelial cancer. Although gene association network analysis demonstrated gene expression profile changes in the liver of human T253 knock-in mice after acute AAI exposure, to date, whether AM causes hepatic tumorigenesis is still not confirmed. Here, we show that hepatic premalignant alterations appeared in canines after a 10 -day AAI oral administration (3 mg/kg/day). We observed c-Myc oncoprotein and oncofeta] RNA-binding protein Lin28B overexpressions accompanied by cancer progenitor-like cell formation in the liver by AM exposure, Meanwhile, we found that forkhead box 01 (FOXO1) was robustly phosphorylated, thereby shuttling into the cytoplasm of hepatocytes. Furthermore, utilizing microarray and qRT-PCR analysis, we confirmed that microRNA expression significantly dysregulated hi the liver treated with AAI. Among them, we particularly focused on the members in let-7 miRNAs and rniR23a clusters, the downstream of c-Myc and 1L6 receptor (IL6R,611) signaling pathway linking the premalignant alteration. Strikingly, when IL6 was added in vitro, 11,614,/111NF-kappa B signaling activation contributed to the increase of FOXO1 phosphorylalion by the let -7b inhibitor. Therefore, it highlights the new insight into the interplay of the network in hepatic turnorigenesis by AA1 exposure, and also suggests that anti-premalignant therapy may be crucial for preventing AAI-induced hepatocarcinogenesis. Cancer Prev Res (C) 2016 AACR

In the city that never sleeps, great science never takes a break. On 15 January 2016, the 'New York Symposium on Quantitative Biology of the Cell', a one-day local meeting of the American Society for Cell Biology (ASCB), took place at Columbia University Medical Center in upper Manhattan. Focusing on the quantitative understanding of cellular and multicellular systems, this meeting created an otherwise rare opportunity for interaction among scientists at various career levels with differing but complementary backgrounds. Highlighting cutting-edge experimental measurements and theoretical modeling, the symposium broke the barrier between disciplines and ignited a hopefully continuing regional dialogue on the emergent topic of quantitative biology of the cell.

In vivo imaging provides unprecedented access to the dynamic behavior of cellular and subcellular structures in their natural context. Performing such imaging experiments in higher vertebrates such as mammals generally requires surgical access to the system under study. The optical accessibility of embryonic and larval zebrafish allows such invasive procedures to be circumvented and permits imaging in the intact organism. Indeed the zebrafish is now a well-established model to visualize dynamic cellular behaviors using in vivo microscopy in a wide range of developmental contexts from proliferation to migration and differentiation. A more recent development is the increasing use of zebrafish to study subcellular events including mitochondrial trafficking and centrosome dynamics. The relative ease with which these subcellular structures can be genetically labeled by fluorescent proteins and the use of light microscopy techniques to image them is transforming the zebrafish into an in vivo model of cell biology. Here we describe methods to generate genetic constructs that fluorescently label organelles, highlighting mitochondria and centrosomes as specific examples. We use the bipartite Gal4-UAS system in multiple configurations to restrict expression to specific cell-types and provide protocols to generate transiently expressing and stable transgenic fish. Finally, we provide guidelines for choosing light microscopy methods that are most suitable for imaging subcellular dynamics.

Group 2 innate lymphoid cells (ILC2) include IL-5- and IL-13-producing CRTh2(+)CD127(+) cells that are implicated in early protective immunity at mucosal surfaces. Whereas functional plasticity has been demonstrated for both human and mouse ILC3 subsets that can reversibly give rise to IFN-gamma-producing ILC1, plasticity of human or mouse ILC2 has not been shown. Here, we analyze the phenotypic and functional heterogeneity of human peripheral blood ILC2. Although subsets of human CRTh2(+) ILC2 differentially express CD117 (c-kit receptor), some ILC2 surface phenotypes are unstable and can be modulated in vitro. Surprisingly, human IL-13(+) ILC2 can acquire the capacity to produce IFN-gamma, thereby generating plastic ILC2. ILC2 cultures demonstrated that IFN-gamma(+) ILC2 clones could be derived and were stably associated with increased T-BET expression. The inductive mechanism for ILC2 plasticity was mapped to the IL-12-IL-12R signaling pathway and was confirmed through analysis of patients with Mendelian susceptibility to mycobacterial disease due to IL-12R beta 1 deficiencies that failed to generate plastic ILC2. We also detected IL-13(+)IFN-gamma(+) ILC2 ex vivo in intestinal samples from Crohn's disease patients. These results demonstrate cytokine production plasticity for human ILC2 and further suggest that environmental cues can dictate ILC phenotype and function for these tissue-resident innate effector cells.

Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase a (pola)/primase- dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. We identified a homozygous POT1 S322L substitution (POT1(CP)) in two siblings with CP. POT1(CP) induced a proliferative arrest that could be bypassed by telomerase. POT1CP was expressed at normal levels, bound TPP1 and telomeres, and blocked ATR signaling. POT1(CP) was defective in regulating telomerase, leading to telomere elongation rather than the telomere shortening observed in other telomeropathies. POT1(CP) was also defective in the maintenance of the telomeric C strand, causing extended 3' overhangs and stochastic telomere truncations that could be healed by telomerase. Consistent with shortening of the telomeric C strand, metaphase chromosomes showed loss of telomeres synthesized by leading strand DNA synthesis. We propose that CP is caused by a defect in POT1/CST-dependent telomere fill-in. We further propose that deficiency in the fill-in step generates truncated telomeres that halt proliferation in cells lacking telomerase, whereas, in tissues expressing telomerase (e.g., bone marrow), the truncations are healed. The proposed etiology can explain why CP presents with features distinct from those associated with telomerase defects (e.g., dyskeratosis congenita).

Testosterone has in recent years been proven essential for normal growth and maturation of small growing follicles. Concomitantly, low functional ovarian reserve (LFOR), characterized by a small growing follicle pool, has been associated with low testosterone levels, which can be of ovarian and/or adrenal origin. In this study we, therefore, investigated whether peripheral sex steroid precursors and testosterone levels potentially reflect on adrenal function. In a retrospective cohort study of 355 consecutive infertile women, who presented to an academically affiliated fertility center in New York City, we investigated in a series of statistical models whether low peripheral sex steroid precursors and testosterone are associated with peripheral cortisol (C) levels, reflecting adrenal function. To determine potential correlations, we investigated the dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione (AD), total testosterone (TT), free testosterone (FT); sex hormone binding globulin (SHBG), anti-Mullerian hormone (AMH), thyroid stimulating hormone (TSH) and C in a series of multivariate and logistic regression analyses, utilizing C either as a continuous variable or with cut off <5.0 mu g/dL, and TT only as a continuous variable. Practically all models demonstrated significant predictability of peripheral sex hormone precursors for C levels, with DHEA demonstrating the strongest and most consistent predictability as an individual parameter and as part of the DHEAS/DHEA ratio. We conclude that in infertile women peripheral sex hormone precursors, especially DHEA, reflect C levels and, therefore, adrenal function. In infertile women, at all ages low levels of sex hormone precursors, therefore, should be considered indications for further adrenal assessments. (C) 2016 Elsevier Ltd. All rights reserved.

Linguistic meaning has long been recognized to be highly context-dependent. Quantifiers like many and some provide a particularly clear example of context-dependence. For example, the interpretation of quantifiers requires listeners to determine the relevant domain and scale. We focus on another type of context-dependence that quantifiers share with other lexical items: talker variability. Different talkers might use quantifiers with different interpretations in mind. We used a web-based crowdsourcing paradigm to study participants' expectations about the use of many and some based on recent exposure. We first established that the mapping of some and many onto quantities (candies in a bowl) is variable both within and between participants. We then examined whether and how listeners' expectations about quantifier use adapts with exposure to talkers who use quantifiers in different ways. The results demonstrate that listeners can adapt to talker-specific biases in both how often and with what intended meaning many and some are used. (C) 2015 Elsevier Inc. All rights reserved.

The first search for a heavy charged vector boson in the final state with a tau lepton and a neutrino is reported, using 19.7 fb(-1) of LHC data at root s = 8 TeV. A signal would appear as an excess of events with high transverse mass, where the standard model background is low. No excess is observed. Limits are set on a model in which the W' decays preferentially to fermions of the third generation. These results substantially extend previous constraints on this model. Masses below 2.0 to 2.7 TeV are excluded, depending on the model parameters. In addition, the existence of a W' boson with universal fermion couplings is excluded at 95% confidence level, for W' masses below 2.7 TeV. For further reinterpretation a model-independent limit on potential signals for various transverse mass thresholds is also presented. (C) 2016 CERN for the benefit of the CMS Collaboration. Published by Elsevier B.V. This is an open access article under the CC BY license.

We, in this manuscript, address the fact that increasing numbers of published studies in reproductive medicine selectively report outcomes for only favorably selected patients; while failing to note that, so reported outcome data,therefore, cannot be applied to unselected patient populations. Almost all favorablepatient selection methods, starting with prolonged embryo culture to blastocyst stage, have, thus, been widely misrepresented in the literature since they almost universally report outcomes only in reference to embryo transfer. These outcome reports, however, do not include outcomes for poorer prognosis patients who do not reach embryo transfer. Study outcomes are universally applicable only if performed in unselected patient populations and reported with reference point cycle start (intent to treat). All other studies greatly exaggerate clinical pregnancy and live birth rates if applied to general populations, unless specifically noting that they can be extrapolated only to women who reach embryo transfer.