A solution to the misrepresentations of CO2-equivalent emissions of short-lived climate pollutants under ambitious mitigation

While cumulative carbon dioxide (CO2) emissions dominate anthropogenic warming over centuries, temperatures over the coming decades are also strongly affected by short-lived climate pollutants (SLCPs), complicating the estimation of cumulative emission budgets for ambitious mitigation goals. Using conventional Global Warming Potentials (GWPs) to convert SLCPs to “CO2-equivalent” emissions misrepresents their impact on global temperature. Here we show that peak warming under a range of mitigation scenarios is determined by a linear combination of cumulative CO2 emissions to the time of peak warming and non-CO2 radiative forcing immediately prior to that time. This may be understood by expressing aggregate non-CO2 forcing as cumulative CO2 forcing-equivalent (CO2-fe) emissions. We show further that contributions to CO2-fe emissions are well approximated by a new usage of GWP, denoted GWP*, which relates cumulative CO2 emissions to date with the current rate of emission of SLCPs. GWP* accurately indicates the impact of emissions of both long-lived and short-lived pollutants on radiative forcing and temperatures over a wide range of timescales, including under ambitious mitigation when conventional GWPs fail. Measured by GWP*,implementing the Paris Agreement would reduce the expected rate of warming in 2030 by 28% relative to a No Policy scenario. Expressing mitigation efforts in terms of their impact on future cumulative emissions aggregated using GWP* would relate them directly to contributions to future warming, better informing both burden-sharing discussions and long-term policies and measures in pursuit of ambitious global temperature goals

A human cancer-associated truncation of MBD4 causes dominant negative impairment of DNA repair in colon cancer cells

MBD4 binds to methylated DNA and acts as a thymine DNA glycosylase in base excision repair. Deficiency of MBD4 in mice enhances mutation at CpG sites and alters apoptosis in response to DNA damage, but does not increase tumorigenesis in mismatch repair-deficient mice. However, in humans, frameshift mutation of MBD4, rather than deletion, is what occurs in up to 43% of microsatellite unstable colon cancers. There is no murine equivalent of this mutation. We now show that recombinant truncated MBD4 (MBD4tru) inhibits glycosylase activities of normal MBD4 or Uracil DNA glycosylase in cell-free assays as a dominant negative effect. Furthermore, overexpression of MBD4tru in Big Blue (lacI)-transfected, MSI human colorectal carcinoma cells doubled mutation frequency, indicating that the modest dominant negative effect on DNA repair can occur in living cells in short-term experiments. Intriguingly, the whole mutation spectrum was increased, not only at CpG sites, suggesting that truncated MBD4 has a more widespread effect on genomic stability. This demonstration of a dominant negative effect may be of significance in tumour progression and acquisition of drug resistance

New use of global warming potentials to compare cumulative and short-lived climate pollutants

Parties to the United Nations Framework Convention on Climate Change (UNFCCC) have requested guidance on common greenhouse gas metrics in accounting for Nationally determined contributions (NDCs) to emission reductions1. Metric choice can affect the relative emphasis placed on reductions of ‘cumulative climate pollutants’ such as carbon dioxide versus ‘short-lived climate pollutants’ (SLCPs), including methane and black carbon2, 3, 4, 5, 6. Here we show that the widely used 100-year global warming potential (GWP100) effectively measures the relative impact of both cumulative pollutants and SLCPs on realized warming 20–40 years after the time of emission. If the overall goal of climate policy is to limit peak warming, GWP100 therefore overstates the importance of current SLCP emissions unless stringent and immediate reductions of all climate pollutants result in temperatures nearing their peak soon after mid-century7, 8, 9, 10, which may be necessary to limit warming to “well below 2 °C” (ref. 1). The GWP100 can be used to approximately equate a one-off pulse emission of a cumulative pollutant and an indefinitely sustained change in the rate of emission of an SLCP11, 12, 13. The climate implications of traditional CO2-equivalent targets are ambiguous unless contributions from cumulative pollutants and SLCPs are specified separately

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Recommended temperature metrics for carbon budget estimates, model evaluation and climate policy

Recent estimates of the amount of carbon dioxide that can still be emitted while achieving the Paris Agreement temperature goals are larger than previously thought. One potential reason for these larger estimates may be the different temperature metrics used to estimate the observed global mean warming for the historical period, as they affect the size of the remaining carbon budget. Here we explain the reasons behind these remaining carbon budget increases, and discuss how methodological choices of the global mean temperature metric and the reference period influence estimates of the remaining carbon budget. We argue that the choice of the temperature metric should depend on the domain of application. For scientific estimates of total or remaining carbon budgets, globally averaged surface air temperature estimates should be used consistently for the past and the future. However, when used to inform the achievement of the Paris Agreement goal, a temperature metric consistent with the science that was underlying and directly informed the Paris Agreement should be applied. The resulting remaining carbon budgets should be calculated using the appropriate metric or adjusted to reflect these differences among temperature metrics. Transparency and understanding of the implications of such choices are crucial to providing useful information that can bridge the science–policy gap

Haemonchus contortus Acetylcholine Receptors of the DEG-3 Subfamily and Their Role in Sensitivity to Monepantel

Gastro-intestinal nematodes in ruminants, especially Haemonchus contortus, are a global threat to sheep and cattle farming. The emergence of drug resistance, and even multi-drug resistance to the currently available classes of broad spectrum anthelmintics, further stresses the need for new drugs active against gastro-intestinal nematodes. A novel chemical class of synthetic anthelmintics, the Amino-Acetonitrile Derivatives (AADs), was recently discovered and the drug candidate AAD-1566 (monepantel) was chosen for further development. Studies with Caenorhabditis elegans suggested that the AADs act via nicotinic acetylcholine receptors (nAChR) of the nematode-specific DEG-3 subfamily. Here we identify nAChR genes of the DEG-3 subfamily from H. contortus and investigate their role in AAD sensitivity. Using a novel in vitro selection procedure, mutant H. contortus populations of reduced sensitivity to AAD-1566 were obtained. Sequencing of full-length nAChR coding sequences from AAD-susceptible H. contortus and their AAD-1566-mutant progeny revealed 2 genes to be affected. In the gene monepantel-1 (Hco-mptl-1, formerly named Hc-acr-23H), a panel of mutations was observed exclusively in the AAD-mutant nematodes, including deletions at intron-exon boundaries that result in mis-spliced transcripts and premature stop codons. In the gene Hco-des-2H, the same 135 bp insertion in the 5′ UTR created additional, out of frame start codons in 2 independent H. contortus AAD-mutants. Furthermore, the AAD mutants exhibited altered expression levels of the DEG-3 subfamily nAChR genes Hco-mptl-1, Hco-des-2H and Hco-deg-3H as quantified by real-time PCR. These results indicate that Hco-MPTL-1 and other nAChR subunits of the DEG-3 subfamily constitute a target for AAD action against H. contortus and that loss-of-function mutations in the corresponding genes may reduce the sensitivity to AADs

Expression of cell cycle proteins in male breast carcinoma

<p>Abstract</p> <p>Introduction</p> <p>Male breast cancer (MBC) is a rare, yet potentially aggressive disease. Although literature regarding female breast cancer (FBC) is extensive, little is known about the etiopathogenesis of male breast cancer. Studies from our laboratory show that MBCs have a distinct immunophenotypic profile, suggesting that the etiopathogenesis of MBC is different from FBCs. The aim of this study was to evaluate and correlate the immunohistochemical expression of cell cycle proteins in male breast carcinoma to significant clinico-biological endpoints.</p> <p>Methods</p> <p>75 cases of MBC were identified using the records of the Saskatchewan Cancer Agency over 26 years (1970-1996). Cases were reviewed and analyzed for the immunohistochemical expression of PCNA, Ki67, p27, p16, p57, p21, cyclin-D1 and c-myc and correlated to clinico-biological endpoints of tumor size, node status, stage of the disease, and disease free survival (DFS).</p> <p>Results</p> <p>Decreased DFS was observed in the majority of tumors that overexpressed PCNA (98%, p = 0.004). The overexpression of PCNA was inversely correlated to the expression of Ki67 which was predominantly negative (78.3%). Cyclin D1 was overexpressed in 83.7% of cases. Cyclin D1 positive tumors were smaller than 2 cm (55.6%, p = 0.005), had a low incidence of lymph node metastasis (38.2%, p = 0.04) and were associated with increased DFS of >150 months (p = 0.04). Overexpression of c-myc (90%) was linked with a higher incidence of node negativity (58.3%, p = 0.006) and increased DFS (p = 0.04). p27 over expression was associated with decreased lymph node metastasis (p = 0.04). P21 and p57 positive tumors were related to decreased DFS (p = 0.04). Though p16 was overexpressed in 76.6%, this did not reach statistical significance with DFS (p = 0.06) or nodal status (p = 0.07).</p> <p>Conclusion</p> <p>Aberrant cell cycle protein expression supports our view that these are important pathways involved in the etiopathogenesis of MBC. Tumors with overexpression of Cyclin D1 and c-myc had better outcomes, in contrast to tumors with overexpression of p21, p57, and PCNA with significantly worse outcomes. P27 appears to be a predictive marker for lymph nodal status. Such observation strongly suggests that dysregulation of cell cycle proteins may play a unique role in the initiation and progression of disease in male breast cancer. Such findings open up new avenues for the treatment of MBC as a suitable candidate for novel CDK-based anticancer therapies in the future.</p

Utilization patterns of Chinese medicine and Western medicine under the National Health Insurance Program in Taiwan, a population-based study from 1997 to 2003

<p>Abstract</p> <p>Background</p> <p>In 1995, Taiwan has launched a national health-care system (the National Health Insurance Program, NHI) covering the use of both Western medicine (WM) and Chinese medicine (CM). This population-based study was conducted to understand the role of CM in this dual medical system by determining the utilization patterns of CM and WM and to analyze the demographic characteristics and primary indications influencing the choice of the medical services for the development of strategies to enhance the appropriate use and reduce unnecessary use of CM.</p> <p>Methods</p> <p>This study used the NHI sample files from 1997 to 2003 consisting of comprehensive utilization and enrolment information for a random sample of 200,432 NHI beneficiaries of the total enrolees from 1995 to 2000. A total of 136,720 subjects with valid and complete enrolment and utilization data were included in this study. The logistic regression method was employed to estimate the odds ratios (ORs) for utilization of CM and WM. The usage, frequency of services, and primary indications for CM and WM were evaluated. A significance level of α = 0.05 was selected.</p> <p>Results</p> <p>Compared with WM, the odds of CM increased from 1997 to 2003. The odds of using CM (OR = 1.48; 95% CI: 1.45–1.50; p < 0.001) and WM (OR = 1.74; 95% CI: 1.72–1.77; p < 0.001) were higher in females and that of CM increased with age to a peak in the 45–54-year-group (OR = 1.75; 95% CI: 1.68–1.82; p < 0.001) and WM (OR = 1.09; 95% CI: 1.05–1.13; p < 0.001) in the elderly subjects (≥ 65 years). The odds of CM and WM were similar in all income groups. However, those of CM were higher in Central (OR = 1.65; 95% CI: 1.56–1.74; p < 0.001) and Southern Taiwan (OR = 1.18; 95% CI: 1.12–1.25; p < 0.001) and lower in the remote areas (OR = 0.57; 95% CI: 0.52–0.63; p < 0.001). Most of the patients had one ambulatory visit of both medical services annually. However, the utilization of WM predominated over CM. Over 90% of CM service was provided by clinics, whereas over 60% of WM service by hospitals. Diseases of the respiratory system was the most frequent primary indication in CM and WM. Herbal medication was the most commonly used form of CM (68.4–72.7%).</p> <p>Conclusion</p> <p>In recent years, there is an increasing trend in the utilization of CM in Taiwan. This increasing trend may be due to the covering of CM in the national health insurance system.</p

Both Geography and Ecology Contribute to Mating Isolation in Guppies

Local adaptation to different environments can promote mating isolation – either as an incidental by-product of trait divergence, or as a result of selection to avoid maladaptive mating. Numerous recent empirical examples point to the common influence of divergent natural selection on speciation based largely on evidence of strong pre-mating isolation between populations from different habitat types. Accumulating evidence for natural selection's influence on speciation is therefore no longer a challenge. The difficulty, rather, is in determining the mechanisms involved in the progress of adaptive divergence to speciation once barriers to gene flow are already present. Here, we present results of both laboratory and field experiments with Trinidadian guppies (Poecilia reticulata) from different environments, who do not show complete reproductive isolation despite adaptive divergence. We investigate patterns of mating isolation between populations that do and do not exchange migrants and show evidence for both by-product and reinforcement mechanisms depending on female ecology. Specifically, low-predation females discriminate against all high-predation males thus implying a by-product mechanism, whereas high-predation females only discriminate against low-predation males from further upstream in the same river, implying selection to avoid maladaptive mating. Our study thus confirms that mechanisms of adaptive speciation are not necessarily mutually exclusive and uncovers the complex ecology-geography interactions that underlie the evolution of mating isolation in nature