Search

In response to the coronavirus (COVID-19) pandemic, there has been an increased need for personal and environmental decontamination to aid in curbing transmission of the SARS-CoV-2 virus. Products used for this purpose include sanitizers for hands and disinfectants for surfaces. The active chemical ingredients used in these products, termed antimicrobials, can enter waste streams after application and may be emerging as more prominent environmental contaminants. Even prior to COVID-19, there was recognized need to examine their implications for aquatic biota, which is now made more pressing due to their exaggerated use in response to the pandemic. Our objectives were to identify current antimicrobial active ingredients, quantify their increased use, and determine which may be candidates for further consideration as possible aquatic contaminants. By consulting multiple sources of publicly available information in Canada, we identified current-use antimicrobials from the lists of sanitizers and surface disinfectants approved for use against SARS-CoV-2 by Health Canada and the drug registration database. To estimate the use of sanitizers and disinfectants, we evaluated import quantities and grocery store retail sales of related compounds and products (Statistics Canada) and both lines of evidence supported increased use trends. The list of identified antimicrobials was refined to include only candidates with potential to reach aquatic ecosystems, and information on their environmental concentrations and toxicity to aquatic biota was reviewed. Candidate antimicrobials (n = 32) fell into four main categories: quaternary ammonium compounds (QACs), phenols, acids, and salts. Benzalkonium chloride, a QAC, was the most prominent active ingredient used in both nonalcohol-based hand sanitizers and surface disinfectants. Four QACs followed in prevalence and the next most used antimicrobial was triclosan (hand sanitizers only), an established and regulated environmental contaminant. Little information was found on environmental concentrations of other candidates, suggesting that the majority would fall into the category of emerging contaminants if they enter aquatic systems. Several were classified as acutely or chronically toxic to aquatic biota (Globally Harmonized System), and thus we recommend empirical research begin focusing on environmental monitoring of all candidate antimicrobials as a critical next step, with detection method development first where needed. Keywords: biocide, pharmaceutical and personal care products, PPCP, pandemic, SARS-CoV-2, Canada, COVID-19, antimicrobial En reponse a la pandemie de coronavirus (COVID-19), un besoin accru de decontamination personnelle et environnementale s'est manifeste pour aider a freiner la transmission du virus SRAS-CoV-2. Les produits utilises a cette fin comprennent des assainisseurs pour les mains et des desinfectants pour les surfaces. Les ingredients chimiques actifs utilises dans ces produits, appeles antimicrobiens, peuvent entrer dans les systemes des eaux usees apres leur application et peuvent devenir des contaminants environnementaux plus importants. Avant meme l'avenement de la COVID-19, on reconnaissait qu'il etait necessaire d'examiner leurs implications pour le biote aquatique, ce qui est aujourd'hui rendu plus urgent en raison de leur utilisation exageree en reponse a la pandemie. Nos objectifs consistaient a identifier les ingredients actifs antimicrobiens actuels, a quantifier leur utilisation accrue et a determiner ceux qui pourraient etre consideres comme des contaminants aquatiques potentiels. En consultant de multiples sources d'information publiquement accessibles au Canada, nous avons pu identifieer les antimicrobiens utilises actuellement a partir des listes d'assainisseurs et de desinfectants de surface dont l'utilisation contre le SRAS-CoV-2 a ete approuvee par Sante Canada, et de la base de donnees sur les produits pharmaceutiques. Pour estimer l'utilisation des assainisseurs et des desinfectants, nous avons evalue les quantites importees et les ventes au detail dans les epiceries de composes et de produits connexes (Statistique Canada) et les deux sources de donnees ont confirme les tendances a l'augmentation de l'utilisation. La liste des antimicrobiens identifies a ete affinee pour n'inclure que les candidats susceptibles d'atteindre les ecosystemes aquatiques, et les informations sur leurs concentrations environnementales et leur toxicite pour le biote aquatique ont ete examinees. Les antimicrobiens candidats (n = 32) se repartissent en quatre grandes categories: les composes d'ammonium quaternaire (CAQ), les phenols, les acides et les sels. Le chlorure de benzalkonium, un CAQ, etait l'ingredient actif le plus utilise dans les desinfectants non alcoolises pour les mains et les desinfectants de surface. Quatre CAQ suivaient en prevalence et l'antimicrobien le plus utilise ensuite etait le triclosan (uniquement dans les desinfectants pour les mains), un contaminant environnemental avere et reglemente. Peu d'informations sur les concentrations environnementales des autres candidats etaient accessibles, ce qui suggere que la majorite d'entre eux entreraient dans la categorie des contaminants emergents s'ils penetrent dans les systemes aquatiques. Plusieurs d'entre eux ont ete classes comme presentant une toxicite aigue ou chronique pour le biote aquatique (Systeme general harmonise de classification et d'etiquetage des produits chimiques, SGH). Les auteurs recommandent donc que la recherche empirique commence a se concentrer sur la surveillance environnementale de tous les candidats antimicrobiens comme prochaine etape critique, en commencant par le developpement de methodes de detection si necessaire. Le texte integral de l'article en francais est disponible parmi les documents supplementaires. Mots-cles : biocide, produits pharmaceutiques et de soins personnels, PPSP, pandemie, SRAS-CoV-2, Canada, COVID-19, antimicrobien, 1. Introduction The use of sanitizing and disinfecting products dramatically increased during the COVID-19 pandemic (da Silva et al. 2021; Dhama et al. 2021), and more information on the impacts [...]

A prerequisite to studying the physiological status of wild animals is the ability to obtain blood samples that reflect the condition prior to capture or handling. Based on research in avian taxa, it is recommended that such samples be obtained within 3 min of capture; however, this guideline has not been validated in wild teleosts. The present study addresses the time course of physiological changes in a number of blood metrics across six species of freshwater fish. Fishes were caught using a standardized angling protocol and held in a water-filled trough prior to the collection of a blood sample, via caudal phlebotomy, between 0.5 and 11 min after capture. Changes in whole-blood glucose and lactate concentrations, hematocrit, and plasma cortisol concentrations were assessed. Change-point analyses indicated that blood lactate concentrations and hematocrit did not deviate from baseline values until ~2-5 min of handling for all species, whereas blood glucose concentrations generally did not deviate significantly from baseline over the 11 min test period. In all species, plasma cortisol concentrations began to increase above baseline between ~4 and 8 min after capture. Thus, to ensure that blood samples are representative of baseline conditions across multiple metrics, we recommend that sampling be limited to less than 2 min in teleost fishes. Key words: stress, cortisol, field endocrinology, glucose, lactate, blood sampling, hematocrit, 3 min rule, wild animals, teleost, largemouth bass, Micropterus salmoides, smallmouth bass, Micropterus dolomieu, rock bass, Ambloplites rupestris, pumpkinseed, Lepomis gibbosus, bluegill, Lepomis macrochirus, northern pike, Esox lucius. Une condition préalable à l'étude de l'état physiologique d'animaux sauvages est la capacité d'obtenir des échantillons de sang qui reflètent l'état avant la capture ou la manipulation. À la lumière de travaux de recherche sur des taxons d'oiseaux, il est recommandé que de tels échantillons soient obtenus dans les 3 min suivant la capture. Cette directive n'a toutefois pas été validée pour les téléostéens vivant à l'état sauvage. L'étude s'est penchée sur la chronologie de changements physiologiques pour différents paramètres sanguins pour six espèces de poissons d'eau douce. Les poissons ont été capturés en suivant un protocole normalisé de pêche à la ligne et maintenus dans une cuve remplie d'eau avant le prélèvement d'un échantillon de sang par ponction caudale, de 0,5 à 11 min après la capture. Les variations des concentrations de glucose et de lactate du sang entier, de l'hématocrite et des concentrations de cortisol plasmatique ont été évaluées. Les analyses des points de changement indiquent que les concentrations de lactate du sang et l'hématocrite ne divergent pas des valeurs de référence avant ~2-5 min de manipulation pour toutes les espèces, alors que les concentrations de glucose du sang ne divergent pas significativement, en général, des valeurs de référence pendant toute la période de manipulation de 11 min. Chez toutes les espèces, la concentration de cortisol plasmatique commence à augmenter au-delà de la valeur de référence entre ~4 et 8 min après la capture. Ainsi, pour s'assurer que les échantillons de sang soient représentatifs des conditions de référence pour différents paramètres, nous recommandons que leur prélèvement soit fait dans les 2 min suivant la capture chez les poissons téléostéens. [Traduit par la Rédaction] Mots-clés : stress, cortisol, endocrinologie de terrain, glucose, lactate, prélèvement sanguin, hématocrite, règle de 3 minutes, animaux sauvages, téléostéen, achigan à grande bouche, Micropterus salmoides, achigan à petite bouche, Micropterus dolomieu, crapet de roche, Ambloplites rupestris, crapet-soleil, Lepomis gibbosus, crapet arlequin, Lepomis macrochirus, grand brochet, Esox lucius., Introduction In many vertebrate species, the physiological dynamics of blood have served as an important tool in assessing whole-organism responses to environmental change and stressors. For example, acute increases in [...]

Author(s): Leila Dardaei [1, 2]; Hui Qin Wang [3]; Manrose Singh [1]; Paul Fordjour [3]; Katherine X Shaw [1]; Satoshi Yoda [1, 2]; Grainne Kerr [4]; Kristine Yu [3]; Jinsheng [...]

Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers., Author(s): The Cancer Genome Atlas Research Network; Albert Einstein College of Medicine; Robert D. Burk [1]; Zigui Chen [1]; Analytical Biological Services; Charles Saller [2]; Katherine Tarvin [2]; Barretos Cancer [...]

Abstract: The nonconsumptive consequences of predators on prey behavior, survival, and demography have recently garnered significant attention by ecologists. However, the impacts of top predators on free-ranging prey are challenging [...]

War is an ever-present force that has the potential to alter the biosphere. Here we review the potential consequences of modern war and military activities on ecosystem structure and function. We focus on the effects of direct conflict, nuclear weapons, military training, and military produced contaminants. Overall, the aforementioned activities were found to have overwhelmingly negative effects on ecosystem structure and function. Dramatic habitat alteration, environmental pollution, and disturbance contributed to population declines and biodiversity losses arising from both acute and chronic effects in both terrestrial and aquatic systems. In some instances, even in the face of massive alterations to ecosystem structure, recovery was possible. Interestingly, military activity was beneficial under specific conditions, such as when an exclusion zone was generated that generally resulted in population increases and (or) population recovery; an observation noted in both terrestrial and aquatic systems. Additionally, military technological advances (e.g., GPS technology, drone technology, biotelemetry) have provided conservation scientists with novel tools for research. Because of the challenges associated with conducting research in areas with military activities (e.g., restricted access, hazardous conditions), information pertaining to military impacts on the environment are relatively scarce and are often studied years after military activities have ceased and with no knowledge of baseline conditions. Additional research would help to elucidate the environmental consequences (positive and negative) and thus reveal opportunities for mitigating negative effects while informing the development of optimal strategies for rehabilitation and recovery. Key words: war, biodiversity, ecosystem structure, conflict, military activities, environment, conservation biology. La guerre est une force omnipresente ayant le potentiel d'alterer l'atmosphere. Les auteurs passent en revue les consequences potentielles des activites guerrieres et militaires modernes sur la structure et le fonctionnement des ecosystemes. On met l'accent sur les effets directs et indirects des conflits, des armes nucleaires, des entrainements militaires et des contaminants des produits militaires. Dans l'ensemble, on constate que les activites prealablement mentionnees ont des effets negatifs ecrasants sur la structure et le fonctionnement des ecosystemes. Avec des alterations dramatiques des habitats, la pollution et les perturbations environnementales contribuent au declin des populations et aux pertes de biodiversite provenant des effets aigus et chroniques sur les systemes terrestres aussi bien qu'aquatiques. Tout de meme dans certains cas, en presence d'alterations massives de la structure des ecosystemes, la recuperation s'est averee possible. Il est interessant de noter qu'une activite militaire fut benefique sous des conditions specifiques telles que la creation d'une zone d'exclusion, en generant des augmentations generales des populations/ou une reprise des populations; ceci fut observe en milieux terrestres aussi bien qu'aquatiques. De plus, les avances des technologies militaires (p. ex. la technologie GPS, les drones, la biotelemetrie) ont fourni aux scientifiques de la conservation de nouveaux outils pour la recherche. Compte tenu des defis associes avec la conduite de recherches dans les sites d'activites militaires (p. ex. acces restreint, conditions dangereuses) les informations concernant les impacts militaires sur l'environnement sont relativement rares et ne sont etudiees qu'apres nombreuses annees apres la fin les activites militaires sans connaissance des conditions des lignes de base au depart. En plus, la recherche aiderait a elucider les consequences environnementales (positives et negatives), revelant ainsi des opportunites pour mitiger les effets negatifs, tout en fournissant des informations pour le developpement de strategies optimales pour la recuperation et la rehabilitation. [Traduit par la Redaction] Mots-cles: guerre, biodiversite, structure des ecosystemes, conflit, activites militaires, environnement, biologie de la conservation., Introduction Conflict has been an ever-present aspect of human civilization. Indeed, the manifestation of conflict in direct combat and military engagements has continuously plagued the world throughout the 20th century [...]

Cancer is a disease potentiated by mutations in somatic cells. Cancer mutations are not distributed uniformly along the human genome. Instead, different human genomic regions vary by up to fivefold in the local density of cancer somatic mutations (1), posing a fundamental problem for statistical methods used in cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape (1-5). However, both somatic mutagenesis and epigenomic features are highly cell-type-specific (6,7). We investigated the distribution of mutations in multiple independent samples of diverse cancer types and compared them to cell-type-specific epigenomic features. Here we show that chromatin accessibility and modification, together with replication timing, explain up to 86% of the variance in mutation rates along cancer genomes. The best predictors of local somatic mutation density are epigenomic features derived from the most likely cell type of origin of the corresponding malignancy. Moreover, we find that cell-of-origin chromatin features are much stronger determinants of cancer mutation profiles than chromatin features of matched cancer cell lines. Furthermore, we show that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome. Thus, the DNA sequence of a cancer genome encompasses a wealth of information about the identity and epigenomic features of its cell of origin., Recent studies have begun to address the underlying causes of cancer mutational heterogeneity by comparing mutation rate variation to the distribution of sequence features, gene expression and epigenetic marks along [...]

The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs. The Cancer Genome Atlas presents an integrative genome-wide analysis of genetic alterations in 279 head and neck squamous cell carcinomas (HNSCCs), which are classified by human papillomavirus (HPV) status; alterations in EGFR, FGFR, PIK3CA and cyclin-dependent kinases are shown to represent candidate targets for therapeutic intervention in most HNSCCs. Large-scale analysis of head and neck cancers Squamous cell head and neck cancer is one of the most common and deadly cancers. Despite initial responses to combinations of surgery, radiation and chemotherapy, approximately half of all tumours recur, usually within two years of initial diagnosis. Molecular markers and targeted therapies have had little impact on this disease to date. Here, The Cancer Genome Atlas team presents a detailed genome-wide overview of alterations and highlights critical genetic events of potential biological and clinical significance in head and neck squamous cell carcinomas (HNSCCs) with different human papillomavirus status. Mutational profiles reveal distinct subgroups of HNSCCs. Mutations in EGFR, FGFRs, PIK3CA and cyclin-dependent kinases represent candidate targets for therapeutic intervention in the majority of HNSCCs., Author(s): Michael S. Lawrence [sup.1] , Carrie Sougnez [sup.1] , Lee Lichtenstein [sup.1] , Kristian Cibulskis [sup.1] , Eric Lander [sup.1] , Stacey B. Gabriel [sup.1] , Gad Getz [sup.1] [...]

Translating whole-exome sequencing (WES) for prospective clinical use may have an impact on the care of patients with cancer; however, multiple innovations are necessary for clinical implementation. These include rapid and robust WES of DNA derived from formalin-fixed, paraffin-embedded tumor tissue, analytical output similar to data from frozen samples and clinical interpretation of WES data for prospective use. Here, we describe a prospective clinical WES platform for archival formalin-fixed, paraffin-embedded tumor samples. The platform employs computational methods for effective clinical analysis and interpretation of WES data. When applied retrospectively to 511 exomes, the interpretative framework revealed a 'long tail' of somatic alterations in clinically important genes. Prospective application of this approach identified clinically relevant alterations in 15 out of 16 patients. In one patient, previously undetected findings guided clinical trial enrollment, leading to an objective clinical response. Overall, this methodology may inform the widespread implementation of precision cancer medicine., Massively parallel sequencing approaches such as WES have elucidated the landscape of genetic alterations in many tumor types and revealed biological insights relevant to clinical contexts (1). The increased practical [...]

Although a few cancer genes are mutated in a high proportion of tumours of a given type (>20%), most are mutated at intermediate frequencies (2-20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600-5,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics., Comprehensive knowledge of the genes underlying human cancers is a critical foundation for cancer diagnostics, therapeutics, clinical-trial design and selection of rational combination therapies. It is now possible to use [...]

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies., Author(s): The Cancer Genome Atlas Research Network; Analysis Working Group: Asan University; Jihun Kim [1]; BC Cancer Agency; Reanne Bowlby [2]; Andrew J. Mungall [2]; A. Gordon Robertson [2]; Brigham [...]

Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival (1,2). Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus [...]

Because of the high risk of recurrence in high-grade serous ovarian carcinoma (HGS-OvCa), the development of outcome predictors could be valuable for patient stratification. Using the catalog of The Cancer [...]

Cancer is principally considered a genetic disease, and numerous mutations are thought essential to drive its growth. However, the existence of genomically stable cancers and the emergence of mutations in [...]

Author(s): Shantanu Banerji [1, 2, 3, 15, 16]; Kristian Cibulskis [1, 16]; Claudia Rangel-Escareno [4, 16]; Kristin K. Brown [5, 16]; Scott L. Carter [1]; Abbie M. Frederick [1]; Michael [...]

A better understanding of the genetic changes that enable cancers to spread is crucial. A comprehensive study of whole-genome sequences from metastatic cancer will help researchers to achieve this goal. Comprehensive analysis of genetic changes across metastatic cancers., Author(s): Jillian F. Wise, Michael S. Lawrence Author Affiliations: Huge whole-genome study of human metastatic cancers The major cause of cancer-related deaths is the spread of cancer cells from their [...]

The C-terminal segment of the human insulin receptor a-chain (designated [alpha]CT) is critical to insulin binding as has been previously demonstrated by alanine scanning mutagenesis and photo-cross-linking. To date no information regarding the structure of this segment within the receptor has been available. We employ here the technique of thermal-factor sharpening to enhance the interpretability of the electron-density maps associated with the earlier crystal structure of the human insulin receptor ectodomain. The [alpha]CT segment is now resolved as being engaged with the central [beta]-sheet of the first leucine-rich repeat (L1) domain of the receptor. The segment is a-helical in conformation and extends 11 residues N-terminal of the classical [alpha]CT segment boundary originally defined by peptide mapping. This tandem structural element ([alpha]CT-L1) thus defines the intact primary insulin-binding surface of the apo-receptor. The structure, together with isothermal titration calorimetry data of mutant [alpha]CT peptides binding to an insulin minireceptor, leads to the conclusion that putative 'insulin-mimetic' peptides in the literature act at least in part as mimics of the [alpha]CT segment as well as of insulin. Photo-cross-linking by novel bifunctional insulin derivatives demonstrates that the interaction of insulin with the [alpha]CT segment and the L1 domain occurs in trans, i.e., these components of the primary binding site are contributed by alternate [alpha]-chains within the insulin receptor homodimer. The tandem structural element defines a new target for the design of insulin agonists for the treatment of diabetes mellitus. diabetes | IGF-1 receptor | insulin binding | photo-cross-linking | protein crystallography doi/ 10.1073/pnas.1001813107

During the onset of diabetes, pancreatic [beta] cells become unable to produce sufficient insulin to maintain blood glucose within the normal range. Proinflammatory cytokines have been implicated in impaired [beta] cell function. To understand more about the molecular events that reduce insulin gene transcription, we examined the effects of hyperglycemia alone and together with the proinflammatory cytokine interleukin-1[beta] (IL-1[beta]) on signal transduction pathways that regulate insulin gene transcription. Exposure to IL-1[beta] in fasting glucose activated multiple protein kinases that associate with the insulin gene promoter and transiently increased insulin gene transcription in [beta] cells. In contrast, cells exposed to hyperglycemic conditions were sensitized to the inhibitory actions of IL-1[beta]. Under these conditions, IL-1[beta] caused the association of the same protein kinases, but a different combination of transcription factors with the insulin gene promoter and began to reduce transcription within 2 h; stimulatory factors were lost, RNA polymerase II was lost, and inhibitory factors were bound to the promoter in a kinase-dependent manner. ERK1/2 | histone acetylation | interleukin 1-[beta] doi/10.1073/pnas.0912596106

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations [...]

MAPK pathways regulate transcription through phosphorylation of transcription factors and other DNA-binding proteins. In pancreatic [beta]-cells, ERK1/2 are required for transcription of the insulin gene and several other genes in response to glucose. We show that binding of glucose-sensitive transcription activators and repressors to the insulin gene promoter depends on ERK1/2 activity. We also find that glucose and NGF stimulate the binding of ERK1/2 to the insulin gene and other promoters. An ERK1/2 cascade module, including MEK1/2 and Rsk, are found in complexes bound to these promoters. These findings imply that MAPK-containing signaling complexes are positioned on sensitive promoters with their protein substrates to modulate transcription in situ in response to incoming signals. c-fos | C/EBP-[beta] | ERK1/2 | hyperglycemia | insulin gene transcription

To purchase or authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1540-5915.2008.00190.x Byline: Dilek Onkal (1), M. Sinan Gonul (2), Michael Lawrence (3) Keywords: Decision Support Systems; Factorial Experimental Design; Forecast Adjustments; Forecast Explanations; Judgmental Forecasting; and Laboratory Experiments Abstract: ABSTRACT Forecasts are important components of information systems. They provide a means for knowledge sharing and thus have significant decision-making impact. In many organizations, it is quite common for forecast users to receive predictions that have previously been adjusted by providers or other users of forecasts. Current work investigates some of the factors that may influence the size and propensity of further adjustments on already-adjusted forecasts. Two studies are reported that focus on the potential effects of adjustment framing (Study 1) and the availability of explanations and/or original forecasts alongside the adjusted forecasts (Study 2). Study 1 provides evidence that the interval forecasts that are labeled as 'adjusted' are modified less than the so-called 'original/unadjusted' predictions. Study 2 suggests that the provision of original forecasts and the presence of explanations accompanying the adjusted forecasts serve as significant factors shaping the size and propensity of further modifications. Findings of both studies highlight the importance of forecasting format and user perceptions with critical organizational repercussions. Author Affiliation: (1)Faculty of Business Administration, Bilkent University, 1. Cadde, Ankara 06800, Turkey, e-mail:onkal@bilkent.edu.tr (2)Department of Business Administration, TOBB University of Economics and Technology, Sogutozu Cad. No: 43, Sogutozu, Ankara 06560, Turkey, e-mail:msgonul@etu.edu.tr (3)Australian School of Business, University of New South Wales, West Wing 2nd Floor, Quadrangle Building, Sydney 2052, Australia, e-mail:Michael.Lawrence@unsw.edu.au Article History: [Received: January 2007. Accepted: August 2007.] Article note: ([dagger]) Corresponding author.

Accurate interpretation of recruitment rate measurements of microscale particles, such as cells and microbeads, to biofunctional surfaces is difficult because factors such as uneven ligand distributions, particle collisions, variable particle fluxes, and molecular-scale surface separation distances obfuscate the ability to link the observed particle behavior with the governing nanoscale biophysics. We report the development of a hydrodynamically conditioned micropattern catch strip assay to measure microparticle recruitment kinetics. The assay exploited patterning within microfluidic channels and the mechanostability of selectin bonds to create reaction geometries that confined a microbead flux to within 200 nm of the surface under flow conditions. Systematic control of capillary action enabled the creation of homogeneous or gradient ligand distributions. The method enabled the measurement of particle recruitment rates ([k.sub.eff], [s.sup.-1]) that were primarily determined by the interaction of the biomolecular pair being investigated. The method is therefore well suited for relative measurements of delivery vehicle and cellular recruitment potential as governed by surface-bound molecules.

Genomic analysis of tumours has led to the identification of hundreds of cancer genes on the basis of the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here we perform deep sequencing in 360 primary breast cancers and develop computational methods to identify significantly mutated promoters. Clear signals are found in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbours a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. Our study shows that promoter regions harbour recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. Power analyses indicate that more such regions remain to be discovered through deep sequencing of adequately sized cohorts of patients., Author(s): Esther Rheinbay [1, 2]; Prasanna Parasuraman [2]; Jonna Grimsby [1]; Grace Tiao [1]; Jesse M. Engreitz [1, 3]; Jaegil Kim [1]; Michael S. Lawrence [1, 2]; Amaro Taylor-Weiner [1]; [...]

CHOP-10 (GADD153/DDIT-3) is a bZIP protein involved in differentiation and apoptosis. Its expression is induced in response to stresses such as nutrient deprivation, perturbation of the endoplasmic reticulum, redox imbalance, and UV exposure. Here we show that CHOP expression is induced in cultured pancreatic [beta]-cells maintained in a basal glucose concentration of 5.5 mM and repressed by stimulatory glucose ([greater than or equal to] 11 mM). Both induction and repression of CHOP are dependent on the MAPKs ERK1 and ERK2. Two regulatory composite sites containing overlapping MafA response elements (MARE) and CAAT enhancer binding (CEB) elements regulate transcription in an ERK1/2-dependent manner. One site (MARE-CEB), from -320 to -300 bp in the promoter, represses transcription. The other site (CEB-MARE), from +2,628 to + 2,641 bp in the first intron of the CHOP gene, activates it. MafA can influence transcription of both sites. The MARE-CEB is repressed by MafA, whereas the CEB-MARE site, which is homologous to the A2C1 component of the glucose-sensitive RIPE3b region of the insulin gene promoter, is activated by MafA. These results indicate that ERK 1/2 have dual roles in regulating CHOP gene expression via both promoter and intronic regions, depending on environmental and metabolic stresses imposed on pancreatic [beta]-cells. MafA | intron | extracellular signal-regulated kinase | cellular stress

The insulin receptor (IR) and epidermal growth factor receptor (EGFR; also known as ErbB) families exhibit similarities in the composition of their ectodomains. The past five years have seen structures determined for all members of the EGFR family including some complexes with ligand or monoclonal antibody fragments. These structures have led to a clearer understanding of their mechanism of activation and inhibition. By contrast, obtaining equivalent understanding of the IR family has lagged behind. However, within the past year, structures of partial and complete ectodomains of the IR have been published that show that the extracellular region of the receptor adopts an unexpected 'inverted V' conformation relative to the cell membrane. This is very different from the folded-over (tethered) conformation of the unactivated EGFR and provides insight into the potential mechanism of activation of the IR. The insulin and EGFR families

P-selectin glycoprotein ligand-1 (PSGL-1) has been proposed as an important tethering ligand for E-selectin and is expressed at a modest level on human leukocytes. Sialyl Lewis x ([sLe.sup.x])-like glycans bind to E-selectin and are expressed at a relatively high level on circulating leukocytes. It is unclear whether PSGL-1 has unique biochemical attributes that contribute to its role as an E-selectin ligand. To probe this issue, we conjugated microspheres with either [sLe.sup.x] or PSGL-1 purified from myeloid cells (neutrophils and HL-60) and compared their adhesion to endothelial expressed E-selectin under defined shear conditions. We found that both [sLe.sup.x] and PSGL-1 microspheres adhere to 4 h of IL-l[beta]-activated human umbilical vein endothelial cells predominantly through E-selectin. Analysis of the adhesion revealed that the rate of initial tethering of the PSGL-1 microspheres to E-selectin was significantly greater than the rate of initial tethering of the [sLe.sup.x] microspheres despite the fact that the [sLe.sup.x] microspheres tested had higher ligand densities than the PSGL-1 microspheres. We also found that pretreatment of the PSGL-1 or [sLe.sup.x] microspheres with HECA-452 had no significant effect on initial tethering to E-selectin. These results support the hypotheses that 1) PSGL-1 is a high-efficiency tethering ligand for E-selectin, 2) ligand biochemistry can significantly influence initial tethering to E-selectin, and 3) PSGL-1 tethering to E-selectin can occur via non-HECA-452 reactive epitopes. adhesion; leukocyte; inflammation

The paper reports a study of the impact on user satisfaction and forecast accuracy of user involvement in the design of a forecasting decision support system (FDSS). Two versions of an FDSS were tested via a laboratory study. Version 1, allowed the user control over all aspects of the system including the 'look' of various screen elements and, most importantly, the model to be used could be selected (and tested) from a number of alternative forecasting models provided within the FDSS. In contrast, Version 2 did not allow the user to modify the 'look' of the screen, and also provided no opportunity for model selection: this feature was carded out optimally by the FDSS. The user was told the advantage of optimal model selection. Both versions finished by asking the user to either accept the forecast (displayed as a point on the time-series graph) or to modify it via the mouse if unhappy with it. Results showed a much greater satisfaction with the forecasts provided by Version 1, confirming the importance of user involvement. Users of Version 1, in about half the cases, selected poor models with high forecast error. Where a model close to optimal was selected, the accuracy of Version 1 users greatly outperformed low involvement Version 2 users. Overall, however, the accuracy of the final forecasts for users of Version 1 was slightly inferior to that of users of Version 2. Measurements of ease of use and usefulness showed no real differences between the two versions. Keywords: User involvement; Forecast satisfaction; Forecast accuracy; Laboratory study, 1. Introduction Forecasts form the basis of most company planning, budgeting and decision making [1-3]. If the forecasts are inaccurate, the plans and budgets based on them are likely to [...]

This paper explores, by means of a laboratory study, the ability of a financial DSS of known theoretical merit to improve decision-making for currency and interest rate forecasting where typically the task is to forecast direction of movement and to assess confidence. The study finds that while the decision-making is improved in comparison with a control, most of the potential value of the DSS is lost. In addition, no improvement in confidence assessment is observed. Both the DSS users and the control group exhibit very poor calibration with confidence assessments uncorrelated with accuracy. Keywords: Financial DSS; Forecasting; Direction forecasting; Confidence; DSS assessment

The reversible aldol condensation of pyruvate and N-acetylmannosamine is catalyzed by sialic acid aldolase with an apparent lack of stereospecificity. As part of this reaction, two conformations are formed from the modeling of Schiff base and enamine intermediates in the active site of the protein. The acceptor-aldehyde group is located in different sides of the enamine in the conformations, although the remainder of the substrate has extremely similar geometries.

Leukocyte rolling mediated by P-, E-, L-selectin was analyzed via intravital microscopy and laminar flow assays. Analysis of leukocyte rolling indicated the role of a threshold level of shear force in promoting cell adhesion via P- and E-selectins. P- and L-selectin-dependent leukocyte rolling in the venules of mouse cremaster muscles also required a minimum shear rate. Furthermore, low blood flow velocities reduced rolling leukocyte flux in wild-type and L-selectin-deficient mice.

Selectin-ligand bonds' high mechanical strength allows it to tether to the vessel wall through one or a few bonds as it also allows rolling in response to hydrodynamic drag. The L-selectin molecule on leukocytes tethers to the peripheral node addressin on the high endothelial venules of the lymph nodes to mediate leukocyte rolling and binds to a ligand on neutrophils to mediate rolling of leukocytes over one another. A mechanism for regulation of these interactions, in vitro and in vivo, is described.

Previous studies have shown a tendency among people to rely on their judgment when it comes to business forecasting. Researchers have advanced several theories to explain this phenomenon. One of the few studies on the behavior of judgmental forecasters and their biases have suggested that these forecasters rely on heuristics and exhibit cognitive biases similar to those found in other forecasters. The feasibility of using anchor and adjustment heuristic to describe the behavior of forecasters using real time series is evaluated.

The cloned self-incompatibility (S) gene from Papaver rhoeas, using oligonucleotides that were based on N-terminal amino acid sequence data from stigmatic proteins, exhibited S-specific pollen inhibitory activity. Pollen containing the Si gene revealed pollen inhibitory activity, while pollen without the S gene were not inhibited.

I. INTRODUCTION The United States antidumping law imposes dumping duties on the sale of foreign goods in the United States "at less than its fair value"[3] when an industry in [...], This Article investigates the Court of International Trade's review of International Trade Commission and Department of Commerce International Trade Administration antidumping determinations. Although the relevant statutes make no distinction between the court's standard of review for ITC versus Department of Commerce decisions, this Article concludes, on the basis of an empirical examination of 268 CIT antidumping decisions since 1985, that the CIT gives slightly greater deference to ITC determinations than to Commerce determinations, and offers some thoughts on why this may be so.