Taking the lead: post-2012 climate targets for the North: towards adequate and equitable future climate commitments for industrialised countries

Any definition of adequacy consistent with the objective of the Climate Convention will require increased mitigation efforts in industrialized countries far beyond those levels agreed in Kyoto. This paper, therefore, focuses on future reduction targets for industrialised (Annex I) countries. It starts with an assessment of mid- and long-term targets already adopted in industrialised countries against the backdrop of required emission cuts to keep climate change within tolerable limits. Taking into account their heterogeneous national circumstances, the main part of the paper presents a method for differentiating Annex I countries with a view to assigning future mitigation and financial transfer commitments. This differentiation exercise is based on an analytical approach that was developed in the project “South-North Dialogue – Equity in the Greenhouse". Slightly modifying the original approach the level of reduction targets is determined by the two criteria of “responsibility" and “potential" to mitigate. Obligations to provide financial and technological resources to developing countries, on the other hand, are to be assigned according to the “capability" criteria. --

Modeling IoT-aware Business Processes - A State of the Art Report

This research report presents an analysis of the state of the art of modeling Internet of Things (IoT)-aware business processes. IOT links the physical world to the digital world. Traditionally, we would find information about events and processes in the physical world in the digital world entered by humans and humans using this information to control the physical world. In the IoT paradigm, the physical world is equipped with sensors and actuators to create a direct link with the digital world. Business processes are used to coordinate a complex environment including multiple actors for a common goal, typically in the context of administrative work. In the past few years, we have seen research efforts on the possibilities to model IoT- aware business processes, extending process coordination to real world entities directly. This set of research efforts is relatively small when compared to the overall research effort into the IoT and much of the work is still in the early research stage. To create a basis for a bridge between IoT and BPM, the goal of this report is to collect and analyze the state of the art of existing frameworks for modeling IoT-aware business processes.Comment: 42 page

Type I-E CRISPR-cas systems discriminate target from non-target DNA through base pairing-independent PAM recognition

This is the final version of the article. Available from the publisher via the DOI in this record.Discriminating self and non-self is a universal requirement of immune systems. Adaptive immune systems in prokaryotes are centered around repetitive loci called CRISPRs (clustered regularly interspaced short palindromic repeat), into which invader DNA fragments are incorporated. CRISPR transcripts are processed into small RNAs that guide CRISPR-associated (Cas) proteins to invading nucleic acids by complementary base pairing. However, to avoid autoimmunity it is essential that these RNA-guides exclusively target invading DNA and not complementary DNA sequences (i.e., self-sequences) located in the host's own CRISPR locus. Previous work on the Type III-A CRISPR system from Staphylococcus epidermidis has demonstrated that a portion of the CRISPR RNA-guide sequence is involved in self versus non-self discrimination. This self-avoidance mechanism relies on sensing base pairing between the RNA-guide and sequences flanking the target DNA. To determine if the RNA-guide participates in self versus non-self discrimination in the Type I-E system from Escherichia coli we altered base pairing potential between the RNA-guide and the flanks of DNA targets. Here we demonstrate that Type I-E systems discriminate self from non-self through a base pairing-independent mechanism that strictly relies on the recognition of four unchangeable PAM sequences. In addition, this work reveals that the first base pair between the guide RNA and the PAM nucleotide immediately flanking the target sequence can be disrupted without affecting the interference phenotype. Remarkably, this indicates that base pairing at this position is not involved in foreign DNA recognition. Results in this paper reveal that the Type I-E mechanism of avoiding self sequences and preventing autoimmunity is fundamentally different from that employed by Type III-A systems. We propose the exclusive targeting of PAM-flanked sequences to be termed a target versus non-target discrimination mechanism.This work was financially supported by an NWO Vidi grant to SJJB (864.11.005). RNJ and BW are supported by the National Institutes of Health (GM 103500) and the Montana State University Agricultural Experimental Station. ES, KAD and KS are supported by an NIH grant RO1 GM10407, a program grant in Molecular and Cell Biology from Presidium of Russian Academy of Sciences and a Russian Foundation for Basic Research grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Role of Nucleotide Identity in Effective CRISPR Target Escape Mutations

Prokaryotes use primed CRISPR adaptation to update their memory bank of spacers against invading genetic elements that have escaped CRISPR interference through mutations in their protospacer target site. We previously observed a trend that nucleotide-dependent mismatches between crRNA and the protospacer strongly influence the efficiency of primed CRISPR adaptation. Here we show that guanine-substitutions in the target strand of the protospacer are highly detrimental to CRISPR interference and interference-dependent priming, while cytosine-substitutions are more readily tolerated. Furthermore, we show that this effect is based on strongly decreased binding affinity of the effector complex Cascade for guanine-mismatched targets, while cytosine-mismatched targets only minimally affect target DNA binding. Structural modeling of Cascade-bound targets with mismatches shows that steric clashes of mismatched guanines lead to unfavorable conformations of the RNA-DNA duplex. This effect has strong implications for the natural selection of target site mutations that lead to effective escape from type I CRISPR–Cas systems

Design approaches in technology enhanced learning

Design is a critical to the successful development of any interactive learning environment (ILE). Moreover, in technology enhanced learning (TEL), the design process requires input from many diverse areas of expertise. As such, anyone undertaking tool development is required to directly address the design challenge from multiple perspectives. We provide a motivation and rationale for design approaches for learning technologies that draws upon Simon's seminal proposition of Design Science (Simon, 1969). We then review the application of Design Experiments (Brown, 1992) and Design Patterns (Alexander et al., 1977) and argue that a patterns approach has the potential to address many of the critical challenges faced by learning technologists

Embolic strokes of undetermined source: prevalence and patient features in the ESUS Global Registry

Background: Recent evidence supports that most non-lacunar cryptogenic strokes are embolic. Accordingly, these strokes have been designated as embolic strokes of undetermined source (ESUS). Aims: We undertook an international survey to characterize the frequency and clinical features of ESUS patients across global regions. Methods: Consecutive patients hospitalized for ischemic stroke were retrospectively surveyed from 19 stroke research centers in 19 different countries to collect patients meeting criteria for ESUS. Results: Of 2144 patients with recent ischemic stroke, 351 (16%, 95% CI 15% to 18%) met ESUS criteria, similar across global regions (range 16% to 21%), and an additional 308 (14%) patients had incomplete evaluation required for ESUS diagnosis. The mean age of ESUS patients (62 years; SD = 15) was significantly lower than the 1793 non-ESUS ischemic stroke patients (68 years, p ≤ 0.001). Excluding patients with atrial fibrillation (n = 590, mean age = 75 years), the mean age of the remaining 1203 non-ESUS ischemic stroke patients was 64 years (p = 0.02 vs. ESUS patients). Among ESUS patients, hypertension, diabetes, and prior stroke were present in 64%, 25%, and 17%, respectively. Median NIHSS score was 4 (interquartile range 2–8). At discharge, 90% of ESUS patients received antiplatelet therapy and 7% received anticoagulation. Conclusions: This cross-sectional global sample of patients with recent ischemic stroke shows that one-sixth met criteria for ESUS, with additional ESUS patients likely among those with incomplete diagnostic investigation. ESUS patients were relatively young with mild strokes. Antiplatelet therapy was the standard antithrombotic therapy for secondary stroke prevention in all global regions

Two randomized crossover multicenter studies investigating gastrointestinal symptoms after bread consumption in individuals with noncoeliac wheat sensitivity: do wheat species and fermentation type matter?

Background: Many individuals reduce their bread intake due to the belief that wheat is the cause of their gastrointestinal (GI) symptoms. Different grains and processing methods may impact tolerability. Objective: We investigated the effects of six different types of bread on GI symptoms in individuals with self-reported non-coeliac wheat sensitivity (NCWS). Methods: Two parallel randomised double-blind crossover multicentre studies were conducted. NCWS individuals, in whom coeliac disease and wheat allergy were ruled out, received five slices of (study A, n=20) yeast fermented (YF) or (study B, n=20) sourdough fermented (SF) bread made of bread wheat, spelt or emmer on three separate intervention days. Each test day was preceded by a run-in period of 3 days and separated by a wash-out period of at least 7 days. GI symptoms were evaluated by change in symptom score (test day minus average of the 3-day run-in period) on a 0-100mm visual analogue scale (delta VAS). Responders were defined as an increase in delta VAS of at least 15mm for overall GI symptoms, abdominal discomfort, abdominal pain, bloating and/or flatulence. Results: The overall change in GI symptoms did not differ between breads of different grains (YF p=0.267; SF p=0.144). The number of responders was also comparable for both YF (6 to wheat, 5 to spelt, and 7 to emmer, p=0.761) and SF breads (9 to wheat, 7 to spelt, and 8 to emmer, p=0.761). Conclusion: The majority of NCWS individuals experienced GI symptoms for at least one of the breads, but on a group level, no differences were found between different grain types for either YF or SF breads. Clinical Trial Registry: ClinicalTrials.gov, NCT0408447

Global survey of the frequency of atrial fibrillation-associated stroke: embolic stroke of undetermined source global registry

Background and Purpose—Atrial fibrillation (AF) is increasingly recognized as the single most important cause of disabling ischemic stroke in the elderly. We undertook an international survey to characterize the frequency of AF-associated stroke, methods of AF detection, and patient features. Methods—Consecutive patients hospitalized for ischemic stroke in 2013 to 2014 were surveyed from 19 stroke research centers in 19 different countries. Data were analyzed by global regions and World Bank income levels. Results—Of 2144 patients with ischemic stroke, 590 (28%; 95% confidence interval, 25.6–29.5) had AF-associated stroke, with highest frequencies in North America (35%) and Europe (33%) and lowest in Latin America (17%). Most had a history of AF before stroke (15%) or newly detected AF on electrocardiography (10%); only 2% of patients with ischemic stroke had unsuspected AF detected by poststroke cardiac rhythm monitoring. The mean age and 30-day mortality rate of patients with AF-associated stroke (75 years; SD, 11.5 years; 10%; 95% confidence interval, 7.6–12.6, respectively) were substantially higher than those of patients without AF (64 years; SD, 15.58 years; 4%; 95% confidence interval, 3.3–5.4; P<0.001 for both comparisons). There was a strong positive correlation between the mean age and the frequency of AF (r=0.76; P=0.0002). Conclusions—This cross-sectional global sample of patients with recent ischemic stroke shows a substantial frequency of AF-associated stroke throughout the world in proportion to the mean age of the stroke population. Most AF is identified by history or electrocardiography; the yield of conventional short-duration cardiac rhythm monitoring is relatively low. Patients with AF-associated stroke were typically elderly (>75 years old) and more often women

A rare missense mutation in <i>GJB3</i> (Cx31G45E) is associated with a unique cellular phenotype resulting in necrotic cell death

Erythrokeratodermia variabilis et progressiva (EKV-P) is caused by mutations in either the GJB3 (Cx31) or GJB4 genes (Cx30.3). We identified a rare GJB3 missense mutation, c.134G>A (p.G45E), in two unrelated patients and investigated its cellular characteristics. Expression of Cx31G45E-GFP caused previously undescribed changes within HeLa cells and HaCaT cells, a model human keratinocyte cell line. Cx31WT-GFP localised to the plasma membrane, but expression of Cx31G45E-GFP caused vacuolar expansion of the endoplasmic reticulum (ER), the mutant protein accumulated within the ER membrane and disassembly of the microtubular network occurred. No ER stress responses were evoked. Cx31WT-myc-myc-6xHis and Cx31G45E-GFP co-immunoprecipitated, indicative of heteromeric interaction, but co-expression with Cx31WT-mCherry, Cx26 or Cx30.3 did not mitigate the phenotype. Cx31 and Cx31G45E both co-immunoprecipitated with Cx43, indicating the ability to form heteromeric connexons. WT-Cx31 and Cx43 assembled into large gap junction plaques at points of cell-to-cell contact; Cx31G45E restricted the ability of Cx43 to reach the plasma membrane in both HaCaT cells and HeLa cells stably expressing Cx43 where the proteins strongly co-localised with the vacolourised ER. Cell viability assays identified an increase in cell death in cells expressing Cx31G45E-GFP, which FACS analysis determined was necrotic. Blocking connexin channel function with 18α-glycyrrhetinic acid did not completely rescue necrosis or prevent propidium iodide uptake, suggesting that expression of Cx31G45E-GFP damages the cellular membrane independent of its channel function. Our data suggest that entrapment of Cx43 and necrotic cell death in the epidermis could underlie the EKV skin phenotype

Ukuran Perusahaan, Winner/loser Stock, Debt to Equity Ratio, Dividend Payout Ratio Pengaruh Terhadap Perataan Laba

Income smoothing is an effort in controlling earnings management to increase or decrease the company\u27s earnings to reduce fluctuations in earnings. This study aimed to examine the effect of the firm size, winner/loser stock, debt to equity ratio, dividend payout ratio to income smoothing. The population in this study is a manufacturing company that is listed on the Indonesia Stock Exchange (BEI) in the period 2010-2013. The sample was selected using purposive sampling technique and acquired 29 manufacturing companies as sample with 116 observations. The analysis technique used in this study is a multiple regression analysis using SPSS.Results The investigations showed that the firm size and winner/loser stocks have significant influence on income smoothing, while debt to equity ratio and dividend payout ratio does not significantly affect income smoothing