Oncogene-dependent regulation of autophagic flux in melanoma

Skin cancer is the one of the most diagnosed cancers in the United States with increasing incidence of 6% every year. In 2015, it is estimated 73,870 new cases of melanoma will be identified and 9,480 individuals will die of their disease. While melanoma only accounts for approximately 2.4% of all cancer related deaths and is the 5th leading diagnosed cancer (US) it is the one of the most common cancers in young adults, age 25-29, particularly for young women. Of particular importance, the mean survival rate of patients diagnosed with metastatic melanoma is six months, with five-year survival rates of less than 5%. One reason for the increasing incidence in young adults may be due to the use of indoor tanning. UV exposure causes DNA damage and can induce the activation of a metabolic pathway called autophagy. Autophagy is activated by stress, including DNA damage, and melanoma risk is associated with UV exposure. Here I present three studies investigating oncogene differences in rates of autophagy as well as the relationship of UV exposure and genotypic variants to autophagy. In this project, I determine whether oncogene status in melanoma differentially regulates apoptosis by modifying autophagic flux. The central hypothesis of this project is that cutaneous malignant melanomas (CMM) with BRAF mutations may be autophagy-addicted while tumors with NRAS mutations may be less dependent on autophagy. I found that BRAF/NRAS mutations differentially alter autophagic flux to suppress apoptosis in melanoma. Our results show that oncogene status in melanoma correlates with differential regulation of autophagic flux and that inhibition of autophagy in BRAF mutant melanoma cells results in apoptosis. These data suggest that BRAF mutant melanoma cells suppress apoptosis by modifying autophagic flux and that these cells may be autophagy addicted in order to promote survival. I also determined that proxy autophagy markers LC3 and Beclin1 are associated with UV exposure and clinical stage when evaluating tissue sections from melanoma patients and controls. Surprisingly, the NRAS wide-type sections had elevated LC3 levels when compared to the NRAS mutant tissue sections suggesting that autophagy may be inhibited NRAS in melanoma tumors. These results indicate that autophagic flux varies by tumor stage and is associated with UVR exposure. Finally, I also determined that several SNPs in autophagy-related genes are melanoma prognostic indictors. Of note, one SNP that has previously been shown to be inversely associated with other diseases, with a functional variant which increases disease susceptibility, was inversely associated with Breslow thickness, the most important indicator of melanoma outcome. The work from my study helps address the inconsistencies in the literature regarding autophagy\u27s impact on melanoma progression. Furthermore, these studies provide a basis to investigate the roles of ATG gene SNPs, UV exposure and utophagy in melanoma

A revision of the genus Chaetorellia Hendel (Diptera: Tephritidae) including a new species associated with spotted knapweed, Centaurea maculosa Lam. (Asteraceae)

Chaetorellia acrolophi sp. n. is associated with some European species of the subgenus Acrolophus of Centaurea. It is a potential biocontrol agent of some Acrolophus species that are adventive noxious weeds in North America. Ch. acrolophi sp. n. is described, and a key is provided to all nine species. The confirmed host-plants, knapweed, starthistles and related plants, belong to the genera Centaurea, Carthamus and Chartolepis (Asteraceae), and these are listed. Available biological data are reviewed, and some details of egg, larval and pupal morphology are described. Host-plant choice tests and canonical variates analysis were used to justify the separation of some species and to help identify some populations. The following nomenclatural changes are made (junior synonyms in brackets): Chaetorellia conjuncta (Becker) is removed from synonymy with Ch. succinea (Costa); Ch. hexachaeta australis Hering is raised to specific status; Ch. hestia Hering (=Ch. nigropicta Hering); Ch. loricata (Rondani) (= Ch. mara Hering and Ch. loricata septentrionalis Hering). Questionable synonyms include: Ch. australis Hering (?=Trypeta hexachaeta Loew); Ch. hestia (?= T. vittata Rondani); Chaetostomella cylindrica (Robineau-Desvoidy) (?= Tephritis algira Macquart, which is removed from Chaetorellia

Recovery in Borderline Personality Disorder (BPD): A Qualitative Study of Service Users' Perspectives

PMCID: PMC3355153This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The future starts in the past:embedding learning for sustainability through culture and community in Scotland

Introduction: If sustainability is about imagining and pursuing desired futures, our past history, heritage, and culture will influence the kind of futures we seek and our chosen routes towards them. In Scotland, there is a strong connection between culture, land, and identity; a sense of community; and a perception of work ethic that derive from our biogeography and socio-political journey. Concepts and practises of education have been influenced by the ideas of key thinkers such as the Scot Sir Patrick Geddes, who introduced approaches to education and community through concepts such as “heart, hand, and head”, “think global, act local,” and “place, work, and folk”. This background influenced us in establishing Scotland's United Nations University-recognised Regional Centre of Expertise (RCE) in Education for Sustainable Development (ESD), known locally as “Learning for Sustainability Scotland”. Its initial development ten years ago and subsequent evolution have been built on engaging collaboratively across Scotland and linking formal, non-formal, and informal modes of learning for sustainability. In this paper, we explore how culture and context have influenced the emergence, governance, and activities of RCE Scotland over the past decade.Methods: We developed an analytical framework of possible cultural and contextual influences on Scottish education. We used a Delphi approach to develop a novel and locally relevant definition of ESD when the RCE was established.Results: Analysis of purposively selected RCE Scotland activities against our cultural framework illustrated how they had been influenced by culture or context. We propose that democratic intellect, local and global, and nature-culture connections have informed our initiative.Discussion: We conclude that connection to people, place, and nature influences engagement and action on sustainability, and we suggest that additional sustainability competencies should include physical, emotional, and spiritual aspects of nature connection

The very large G-protein coupled receptor VLGR1: a component of the ankle link complex required for the normal development of auditory hair bundles

Sensory hair bundles in the inner ear are composed of stereocilia that can be interconnected by a variety of different link types, including tip links, horizontal top connectors, shaft connectors, and ankle links. The ankle link antigen is an epitope specifically associated with ankle links and the calycal processes of photoreceptors in chicks. Mass spectrometry and immunoblotting were used to identify this antigen as the avian ortholog of the very large G-protein-coupled receptor VLGR1, the product of the Usher syndrome USH2C (Mass1) locus. Like ankle links, Vlgr1 is expressed transiently around the base of developing hair bundles in mice. Ankle links fail to form in the cochleae of mice carrying a targeted mutation in Vlgr1 (Vlgr1/del7TM), and the bundles become disorganized just after birth. FM1-43 [N-(3-triethylammonium)propyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide] dye loading and whole-cell recordings indicate mechanotransduction is impaired in cochlear, but not vestibular, hair cells of early postnatal Vlgr1/del7TM mutant mice. Auditory brainstem recordings and distortion product measurements indicate that these mice are severely deaf by the third week of life. Hair cells from the basal half of the cochlea are lost in 2-month-old Vlgr1/del7TM mice, and retinal function is mildly abnormal in aged mutants. Our results indicate that Vlgr1 is required for formation of the ankle link complex and the normal development of cochlear hair bundles

Predicting fatigue using countermovement jump force-time signatures:PCA can distinguish neuromuscular versus metabolic fatigue

Purpose This study investigated the relationship between the ground reaction force-time profile of a countermovement jump (CMJ) and fatigue, specifically focusing on predicting the onset of neuromuscular versus metabolic fatigue using the CMJ. Method Ten recreational athletes performed 5 CMJs at time points prior to, immediately following, and at 0.5, 1, 3, 6, 24 and 48 h after training, which comprised repeated sprint sessions of low, moderate, or high workloads. Features of the concentric portion of the CMJ force-time signature at the measurement time points were analysed using Principal Components Analysis (PCA) and functional PCA (fPCA) to better understand fatigue onset given training workload. In addition, Linear Mixed Effects (LME) models were developed to predict the onset of fatigue. Results The first two Principal Components (PCs) using PCA explained 68% of the variation in CMJ features, capturing variation between athletes through weighted combinations of force, concentric time and power. The next two PCs explained 9.9% of the variation and revealed fatigue effects between 6 to 48 h after training for PC3, and contrasting neuromuscular and metabolic fatigue effects in PC4. fPCA supported these findings and further revealed contrasts between metabolic and neuromuscular fatigue effects in the first and second half of the force-time curve in PC3, and a double peak effect in PC4. Subsequently, CMJ measurements up to 0.5 h after training were used to predict relative peak CMJ force, with mean squared errors of 0.013 and 0.015 at 6 and 48 h corresponding to metabolic and neuromuscular fatigue. Conclusion The CMJ was found to provide a strong predictor of neuromuscular and metabolic fatigue, after accounting for force, concentric time and power. This method can be used to assist coaches to individualise future training based on CMJ response to the immediate session

Validity of the WKB Approximation in Calculating the Asymptotic Quasinormal Modes of Black Holes

In this paper, we categorize non-rotating black hole spacetimes based on their pole structure and in each of these categories we determine whether the WKB approximation is a valid approximation for calculating the asymptotic quasinormal modes. We show that Schwarzschild black holes with the Gauss-Bonnet correction belong to the category in which the WKB approximation is invalid for calculating these modes. In this context, we further discuss and clarify some of the ambiguity in the literature surrounding the validity conditions provided for the WKB approximation.Comment: 10 page

Likely Impact of the COVID-19 Pandemic on Newborn Hearing Screening and Follow-up Services in the United States in 2020

This perspective aims to highlight aspects of the Early Hearing Detection and Intervention (EHDI) newborn hearing screening and follow-up processes that were impacted by the COVID-19 pandemic and considers factors that likely impacted follow-up after newborn hearing screening among infants born in the United States during 2020. Efforts to minimize the potential impact of missed or delayed identification of hearing loss in infants and young children will also be discussed to help guide future program improvement activities

Multiple sclerosis risk variants influence the peripheral B-cell compartment early in life in the general population

Background and purpose: Multiple sclerosis (MS) is associated with abnormal B-cell function, and MS genetic risk alleles affect multiple genes that are expressed in B cells. However, how these genetic variants impact the B-cell compartment in early childhood is unclear. In the current study, we aim to assess whether polygenic risk scores (PRSs) for MS are associated with changes in the blood B-cell compartment in children from the general population. Methods: Six-year-old children from the population-based Generation R Study were included. Genotype data were used to calculate MS-PRSs and B-cell subset-enriched MS-PRSs, established by designating risk loci based on expression and function. Analyses of variance were performed to examine the effect of MS-PRSs on total B-cell numbers (n = 1261) as well as naive and memory subsets (n = 675). Results: After correction for multiple testing, no significant associations were observed between MS-PRSs and total B-cell numbers and frequencies of subsets therein. A naive B-cell-MS-PRS (n = 26 variants) was significantly associated with lower relative, but not absolute, naive B-cell numbers (p = 1.03 × 10−4 and p = 0.82, respectively), and higher frequencies and absolute numbers of CD27+ memory B cells (p = 8.83 × 10−4 and p = 4.89 × 10−3, respectively). These associations remained significant after adjustment for Epstein–Barr virus seropositivity and the HLA-DRB1*15:01 genotype. Conclusions: The composition of the blood B-cell compartment is associated with specific naive B-cell-associated MS risk variants during childhood, possibly contributing to MS pathophysiology later in life. Cell subset-specific PRSs may offer a more sensitive tool to define the impact of genetic risk on the immune system in diseases such as MS.</p