The cJUN NH2-terminal kinase (JNK) signaling pathway promotes genome stability and prevents tumor initiation

Breast cancer is the most commonly diagnosed malignancy in women. Analysis of breast cancer genomic DNA indicates frequent loss-of-function mutations in components of the cJUN NH2-terminal kinase (JNK) signaling pathway. Since JNK signaling can promote cell proliferation by activating the AP1 transcription factor, this apparent association of reduced JNK signaling with tumor development was unexpected. We examined the effect of JNK deficiency in the murine breast epithelium. Loss of JNK signaling caused genomic instability and the development of breast cancer. Moreover, JNK deficiency caused widespread early neoplasia and rapid tumor formation in a murine model of breast cancer. This tumor suppressive function was not mediated by a role of JNK in the growth of established tumors, but by a requirement of JNK to prevent tumor initiation. Together, these data identify JNK pathway defects as \u27driver\u27 mutations that promote genome instability and tumor initiation

Interdisciplinary Strategies for Treating Oral Aversions in Children.

Oral aversion is a frequent diagnosis in the pediatric population. For a minority of children, feeding challenges rise to the level of requiring clinical evaluation and intervention. Determining the best evaluation and treatment plan can be challenging, but there is a consensus that treatment for children with a severe oral aversion involves an interdisciplinary approach. Within the team model, multiple strategies have demonstrated effectiveness, including sensorimotor skill building, behavioral modification, hunger provocation, and sensory integration therapy. This tutorial reviews the diagnostic and treatment process for a child with oral aversion, including identification of an underlying etiology, the medical and behavioral evaluation, and formulation of a treatment plan

Next-generation sequencing of advanced prostate cancer treated with androgen-deprivation therapy

<b>Background:</b> Androgen-deprivation therapy (ADT) is standard treatment for locally advanced or metastatic prostate cancer (PCa). Many patients develop castration resistance (castration-resistant PCa [CRPC]) after approximately 2–3 yr, with a poor prognosis. The molecular mechanisms underlying CRPC progression are unclear.<p></p> <b>Objective:</b> To undertake quantitative tumour transcriptome profiling prior to and following ADT to identify functionally important androgen-regulated pathways or genes that may be reactivated in CRPC.<p></p> <b>Design, setting, and participants:</b> RNA sequencing (RNA-seq) was performed on tumour-rich, targeted prostatic biopsies from seven patients with locally advanced or metastatic PCa before and approximately 22 wk after ADT initiation. Differentially regulated genes were identified in treatment pairs and further investigated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on cell lines and immunohistochemistry on a separate CRPC patient cohort. Functional assays were used to determine the effect of pathway modulation on cell phenotypes.<p></p> <b>Outcome measurements and statistical analysis:</b> We searched for gene expression changes affecting key cell signalling pathways that may be targeted as proof of principle in a CRPC in vitro cell line model.<p></p> <b>Results and limitations:</b> We identified ADT-regulated signalling pathways, including the Wnt/β-catenin signalling pathway, and observed overexpression of β-catenin in a subset of CRPC by immunohistochemistry. We validated 6 of 12 (50%) pathway members by qRT-PCR on LNCaP/LNCaP-AI cell RNAs, of which 4 (67%) demonstrated expression changes consistent with RNA-seq data. We show that the tankyrase inhibitor XAV939 (which promotes β-catenin degradation) reduced androgen-independent LNCaP-AI cell line growth compared with androgen-responsive LNCaP cells via an accumulation of cell proportions in the G0/G1 phase and reduction in the S and G2/M phases. Our biopsy protocol did not account for tumour heterogeneity, and pathway inhibition was limited to pharmacologic approaches.<p></p> <b>Conclusions:</b> RNA-seq of paired PCa samples revealed ADT-regulated signalling pathways. Proof-of-principle inhibition of the Wnt/β-catenin signalling pathway specifically delays androgen-independent PCa cell cycle progression and proliferation and warrants further investigation as a potential target for therapy for CRPC.<p></p&gt

Beyond the Thomas-Fermi approximation for a trapped condensed Bose-Einstein gas

Corrections to the zero-temperature Thomas-Fermi description of a dilute interacting condensed Bose-Einstein gas confined in an isotropic harmonic trap arise due to the presence of a boundary layer near the condensate surface. Within the Bogoliubov approximation, the various contributions to the ground-state condensate energy all have terms of order R^{-4}ln R and R^{-4}, where R is the number-dependent dimensionless condensate radius in units of the oscillator length. The zero-order hydrodynamic density-fluctuation amplitudes are extended beyond the Thomas-Fermi radius through the boundary layer to provide a uniform description throughout all space. The first-order correction to the excitation frequencies is shown to be of order R^{-4}.Comment: 12 pages, 2 figures, revtex. Completely revised discussion of the boundary-layer corrections to collective excitations, and two new figures added. To appear in Phys. Rev. A (October, 1998

Evaluation of Fatigue Management Technologies Using Weighted Feature Matrix Method

Operator fatigue is one of the most prevalent root causes of accidents,both on the highway and in workplaces where heavy equipment is used and 12-hour shifts are employed, such as in the mining industry. In response to thisconcern, a growing number of Fatigue Management Technologies (FMT) arebecoming available to help maintain operator alertness and performance levels bydetecting operator fatigue and interfacing with the operator and/or supervisor toprevent accidents and incidents (Williamson et al., 2005, Barr et al., 2005). Inlight of the numerous competing technologies, the research community, as well asindustry, could benefit from the flexible evaluation tool proposed here. It willassist industries as a whole, and corporations more specifically, in identifying thebest FMT solutions for different work and/or driving situations. This project wasspecifically focused on the needs of operators of heavy equipment in the miningindustry, but could also be of value to other like industries where shift work isnecessary and maintaining high levels of alertness are crucial for ensuringworkplace safety and productivity

Carbon dioxide and ocean acidification observations in UK waters. Synthesis report with a focus on 2010–2015

Key messages: 1.1 The process of ocean acidification is now relatively well-documented at the global scale as a long-term trend in the open ocean. However, short-term and spatial variability can be high. 1.2 New datasets made available since Charting Progress 2 make it possible to greatly improve the characterisation of CO2 and ocean acidification in UK waters. 3.1 Recent UK cruise data contribute to large gaps in national and global datasets. 3.2 The new UK measurements confirm that pH is highly variable, therefore it is important to measure consistently to determine any long term trends. 3.3 Over the past 30 years, North Sea pH has decreased at 0.0035±0.0014 pH units per year. 3.4 Upper ocean pH values are highest in spring, lowest in autumn. These changes reflect the seasonal cycles in photosynthesis, respiration (decomposition) and water mixing. 3.5 Carbonate saturation states are minimal in the winter, and lower in 7 more northerly, colder waters. This temperature-dependence could have implications for future warming of the seas. 3.6 Over the annual cycle, North-west European seas are net sinks of CO2. However, during late summer to autumn months, some coastal waters may be significant sources. 3.7 In seasonally-stratified waters, sea-floor organisms naturally experience lower pH and saturation states; they may therefore be more vulnerable to threshold changes. 3.8 Large pH changes (0.5 - 1.0 units) can occur in the top 1 cm of sediment; however, such effects are not well-documented. 3.9 A coupled forecast model estimates the decrease in pH trend within the North Sea to be -0.0036±0.00034 pH units per year, under a high greenhouse gas emissions scenario (RCP 8.5). 3.10 Seasonal estimates from the forecast model demonstrate areas of the North Sea that are particularly vulnerable to aragonite undersaturation

DNA Binding Polyamides and the Importance of DNA Recognition in their use as Gene-Specific and Antiviral Agents

There is a long history for the bioorganic and biomedical use of N-methyl-pyrrole-derived polyamides (PAs) that are higher homologs of natural products such as distamycin A and netropsin. This work has been pursued by many groups, with the Dervan and Sugiyama groups responsible for many breakthroughs. We have studied PAs since about 1999, partly in industry and partly in academia. Early in this program, we reported methods to control cellular uptake of polyamides in cancer cell lines and other cells likely to have multidrug resistance efflux pumps induced. We went on to discover antiviral polyamides active against HPV31, where SAR showed that a minimum binding size of about 10 bp of DNA was necessary for activity. Subsequently we discovered polyamides active against two additional high-risk HPVs, HPV16 and 18, a subset of which showed broad spectrum activity against HPV16, 18 and 31. Aspects of our results presented here are incompatible with reported DNA recognition rules. For example, molecules with the same cognate DNA recognition properties varied from active to inactive against HPVs. We have since pursued the mechanism of action of antiviral polyamides, and polyamides in general, with collaborators at NanoVir, the University of Missouri-St. Louis, and Georgia State University. We describe dramatic consequences of β-alanine positioning even in relatively small, 8-ring polyamides; these results contrast sharply with prior reports. This paper was originally presented by JKB as a Keynote Lecture in the 2nd International Conference on Medicinal Chemistry and Computer Aided Drug Design Conference in Las Vegas, NV, October 2013

Potent and Broad Neutralization of HIV-1 by a Llama Antibody Elicited by Immunization

Llamas (Lama glama) naturally produce heavy chain–only antibodies (Abs) in addition to conventional Abs. The variable regions (VHH) in these heavy chain–only Abs demonstrate comparable affinity and specificity for antigens to conventional immunoglobulins despite their much smaller size. To date, immunizations in humans and animal models have yielded only Abs with limited ability to neutralize HIV-1. In this study, a VHH phagemid library generated from a llama that was multiply immunized with recombinant trimeric HIV-1 envelope proteins (Envs) was screened directly for HIV-1 neutralization. One VHH, L8CJ3 (J3), neutralized 96 of 100 tested HIV-1 strains, encompassing subtypes A, B, C, D, BC, AE, AG, AC, ACD, CD, and G. J3 also potently neutralized chimeric simian-HIV strains with HIV subtypes B and C Env. The sequence of J3 is highly divergent from previous anti–HIV-1 VHH and its own germline sequence. J3 achieves broad and potent neutralization of HIV-1 via interaction with the CD4-binding site of HIV-1 Env. This study may represent a new benchmark for immunogens to be included in B cell–based vaccines and supports the development of VHH as anti–HIV-1 microbicides

A genome annotation-driven approach to cloning the human ORFeome.

We have developed a systematic approach to generating cDNA clones containing full-length open reading frames (ORFs), exploiting knowledge of gene structure from genomic sequence. Each ORF was amplified by PCR from a pool of primary cDNAs, cloned and confirmed by sequencing. We obtained clones representing 70% of genes on human chromosome 22, whereas searching available cDNA clone collections found at best 48% from a single collection and 60% for all collections combined.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

A meta-analysis of the drive for muscularity's relationships with exercise behaviour, disordered eating, supplement consumption, and exercise dependence

We examined the drive for muscularity's (DFM) relationships with exercise behaviour, disordered eating, supplement consumption, and exercise dependence in males. By searching electronic databases, manually reviewing journal tables of contents and retrieved article reference lists, and corresponding with leading researchers, we identified 77 studies. A random effects model was applied to perform analyses and we adjusted results for possible publication bias. The average effect sizes (r) the DFM had with weight training (.31), non-weight training (.11), disordered eating (.30), supplement consumption (.36), and exercise dependence (.43) were significant (P < .05). The relationship between the attitudes and behavioural subscales of the DFM Scale (r = .47) was significant (P < .001). For supplement consumption, moderator analysis indicated that r varied significantly for questionnaire type and participant status (student versus non-student, P < .01). The small to moderate relationships indicate the value of adopting theoretical perspectives allowing the examination of the DFM's role in predicting exercise and dietary behaviour within a broader psychosocial context. Most researchers have studied these relationships in isolation. The relationship between the two DFM subscales implies that the questionnaire total score may better represent a commitment to muscularity rather than a drive per se