This study tests the ability of five Dynamic Global Vegetation Models (DGVMs), forced with observed climatology and atmospheric CO₂, to model the contemporary global carbon cycle. The DGVMs are also ...coupled to a fast 'climate analogue model', based on the Hadley Centre General Circulation Model (GCM), and run into the future for four Special Report Emission Scenarios (SRES): A1FI, A2, B1, B2. Results show that all DGVMs are consistent with the contemporary global land carbon budget. Under the more extreme projections of future environmental change, the responses of the DGVMs diverge markedly. In particular, large uncertainties are associated with the response of tropical vegetation to drought and boreal ecosystems to elevated temperatures and changing soil moisture status. The DGVMs show more divergence in their response to regional changes in climate than to increases in atmospheric CO₂ content. All models simulate a release of land carbon in response to climate, when physiological effects of elevated atmospheric CO₂ on plant production are not considered, implying a positive terrestrial climate-carbon cycle feedback. All DGVMs simulate a reduction in global net primary production (NPP) and a decrease in soil residence time in the tropics and extra-tropics in response to future climate. When both counteracting effects of climate and atmospheric CO₂ on ecosystem function are considered, all the DGVMs simulate cumulative net land carbon uptake over the 21st century for the four SRES emission scenarios. However, for the most extreme A1FI emissions scenario, three out of five DGVMs simulate an annual net source of CO₂ from the land to the atmosphere in the final decades of the 21st century. For this scenario, cumulative land uptake differs by 494 Pg C among DGVMs over the 21st century. This uncertainty is equivalent to over 50 years of anthropogenic emissions at current levels.
N
-acetylcytidine (ac
C) is an ancient and highly conserved RNA modification that is present on tRNA and rRNA and has recently been investigated in eukaryotic mRNA
. However, the distribution, ...dynamics and functions of cytidine acetylation have yet to be fully elucidated. Here we report ac
C-seq, a chemical genomic method for the transcriptome-wide quantitative mapping of ac
C at single-nucleotide resolution. In human and yeast mRNAs, ac
C sites are not detected but can be induced-at a conserved sequence motif-via the ectopic overexpression of eukaryotic acetyltransferase complexes. By contrast, cross-evolutionary profiling revealed unprecedented levels of ac
C across hundreds of residues in rRNA, tRNA, non-coding RNA and mRNA from hyperthermophilic archaea. Ac
C is markedly induced in response to increases in temperature, and acetyltransferase-deficient archaeal strains exhibit temperature-dependent growth defects. Visualization of wild-type and acetyltransferase-deficient archaeal ribosomes by cryo-electron microscopy provided structural insights into the temperature-dependent distribution of ac
C and its potential thermoadaptive role. Our studies quantitatively define the ac
C landscape, providing a technical and conceptual foundation for elucidating the role of this modification in biology and disease
.
The land and ocean absorb on average just over half of the anthropogenic emissions of carbon dioxide (CO2) every year. These CO2 "sinks" are modulated by climate change and variability. Here we use a ...suite of nine dynamic global vegetation models (DGVMs) and four ocean biogeochemical general circulation models (OBGCMs) to estimate trends driven by global and regional climate and atmospheric CO2 in land and oceanic CO2 exchanges with the atmosphere over the period 1990–2009, to attribute these trends to underlying processes in the models, and to quantify the uncertainty and level of inter-model agreement. The models were forced with reconstructed climate fields and observed global atmospheric CO2; land use and land cover changes are not included for the DGVMs. Over the period 1990–2009, the DGVMs simulate a mean global land carbon sink of −2.4 ± 0.7 Pg C yr−1 with a small significant trend of −0.06 ± 0.03 Pg C yr−2 (increasing sink). Over the more limited period 1990–2004, the ocean models simulate a mean ocean sink of −2.2 ± 0.2 Pg C yr−1 with a trend in the net C uptake that is indistinguishable from zero (−0.01 ± 0.02 Pg C yr−2). The two ocean models that extended the simulations until 2009 suggest a slightly stronger, but still small, trend of −0.02 ± 0.01 Pg C yr−2. Trends from land and ocean models compare favourably to the land greenness trends from remote sensing, atmospheric inversion results, and the residual land sink required to close the global carbon budget. Trends in the land sink are driven by increasing net primary production (NPP), whose statistically significant trend of 0.22 ± 0.08 Pg C yr−2 exceeds a significant trend in heterotrophic respiration of 0.16 ± 0.05 Pg C yr−2 – primarily as a consequence of widespread CO2 fertilisation of plant production. Most of the land-based trend in simulated net carbon uptake originates from natural ecosystems in the tropics (−0.04 ± 0.01 Pg C yr−2), with almost no trend over the northern land region, where recent warming and reduced rainfall offsets the positive impact of elevated atmospheric CO2 and changes in growing season length on carbon storage. The small uptake trend in the ocean models emerges because climate variability and change, and in particular increasing sea surface temperatures, tend to counter\\-act the trend in ocean uptake driven by the increase in atmospheric CO2. Large uncertainty remains in the magnitude and sign of modelled carbon trends in several regions, as well as regarding the influence of land use and land cover changes on regional trends.
Infections caused by resistant microorganisms often fail to respond to conventional therapy, resulting in prolonged illness, increased treatment costs and greater risk of death. Consequently, the ...development of novel antimicrobial drugs is becoming more demanding every day since the existing drugs either have too many side-effects or they tend to lose effectiveness due to the selection of resistant strains. In view of these facts, a number of new strategies to obstruct vital biological processes of a microbial cell have emerged; one of these is focused on the use of metal-chelating agents, which are able to selectively disturb the essential metal metabolism of the microorganism by interfering with metal acquisition and bioavailability for crucial reactions. The chelation activity is able to inhibit the biological role of metal-dependent proteins (e.g., metalloproteases and transcription factors), disturbing the microbial cell homeostasis and culminating in the blockage of microbial nutrition, growth and development, cellular differentiation, adhesion to biotic (e.g., extracellular matrix components, cell and/or tissue) and abiotic (e.g., plastic, silicone and acrylic) structures as well as controlling the in vivo infection progression. Interestingly, chelating agents also potentiate the activity of classical antimicrobial compounds. The differences between the microorganism and host in terms of the behavior displayed in the presence of chelating agents could provide exploitable targets for the development of an effective chemotherapy for these diseases. Consequently, metal chelators represent a novel group of antimicrobial agents with potential therapeutic applications. This review will focus on the anti-fungal and anti-protozoan action of the most common chelating agents, deciphering and discussing their mode of action.
Aspartic peptidase inhibitors have shown antimicrobial action against distinct microorganisms. Due to an increase in the occurrence of Chagas' disease/AIDS co-infection, we decided to explore the ...effects of HIV aspartic peptidase inhibitors (HIV-PIs) on Trypanosoma cruzi, the etiologic agent of Chagas' disease.
HIV-PIs presented an anti-proliferative action on epimastigotes of T. cruzi clone Dm28c, with IC50 values ranging from 0.6 to 14 µM. The most effective inhibitors, ritonavir, lopinavir and nelfinavir, also had an anti-proliferative effect against different phylogenetic T. cruzi strains. The HIV-PIs induced some morphological alterations in clone Dm28c epimastigotes, as reduced cell size and swollen of the cellular body. Transmission electron microscopy revealed that the flagellar membrane, mitochondrion and reservosomes are the main targets of HIV-PIs in T. cruzi epimastigotes. Curiously, an increase in the epimastigote-into-trypomastigote differentiation process of clone Dm28c was observed, with many of these parasites presenting morphological alterations including the detachment of flagellum from the cell body. The pre-treatment with the most effective HIV-PIs drastically reduced the interaction process between epimastigotes and the invertebrate vector Rhodnius prolixus. It was also noted that HIV-PIs induced an increase in the expression of gp63-like and calpain-related molecules, and decreased the cruzipain expression in epimastigotes as judged by flow cytometry and immunoblotting assays. The hydrolysis of a cathepsin D fluorogenic substrate was inhibited by all HIV-PIs in a dose-dependent manner, showing that the aspartic peptidase could be a possible target to these drugs. Additionally, we verified that ritonavir, lopinavir and nelfinavir reduced drastically the viability of clone Dm28c trypomastigotes, causing many morphological damages.
The results contribute to understand the possible role of aspartic peptidases in T. cruzi physiology, adding new in vitro insights into the possibility of exploiting the use of HIV-PIs in the clinically relevant forms of the parasite.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mercury has long been recognised as toxic, principally in relation to its effects on humans following acute or prolonged high-level occupational exposures and, in the latter half of the last century, ...from a number of environmental incidents. Recognised target organs are the kidneys, central nervous system and thyroid glands. Recently concern has grown about the potential risks to the human population from current background environmental levels, leading bodies such as the World Health Organisation to call for the reduction or, wherever possible, elimination of the use of mercury. This review considers the strength of the epidemiological evidence on the effects of prolonged low-level exposure to the various forms of mercury.
The limited research base suggests that several of the potential targets of long-term environmental exposure to mercury are similar to those occurring from occupational exposure including the renal, cardiovascular and immune systems. However, the evidence also suggests that, particularly in the case of organic mercury compounds, the most sensitive endpoint is central nervous system toxicity, especially in relation to exposure during the
in utero period and childhood. It also appears that those human populations which have traditionally consumed diets high in seafoods are at greatest risk. While the extent of risk to the general population that may arise from existing environmental exposure levels appears limited, this conclusion is based on an incomplete dataset and therefore the general consensus view that exposure to mercury in its various forms should be minimised where practical, appears to be justified. A number of potential areas of further research are suggested as being pre-requisite to the development of a more rigorous risk assessment.
The treatment for both leishmaniasis and trypanosomiasis, which are severe human infections caused by trypanosomatids belonging to Leishmania and Trypanosoma genera, respectively, is extremely ...limited because of concerns of toxicity and efficacy with the available anti-protozoan drugs, as well as the emergence of drug resistance. Consequently, the urgency for the discovery of new trypanosomatid targets and novel bioactive compounds is particularly necessary. In this context, the investigation of changes in parasite gene expression between drug resistant/sensitive strains and in the up-regulation of virulence-related genes in infective forms has brought to the fore the involvement of calpain-like proteins in several crucial pathophysiological processes performed by trypanosomatids. These studies were encouraged by the publication of the complete genome sequences of three human pathogenic trypanosomatids, Trypanosoma brucei, Trypanosoma cruzi and Leishmania major, which allowed in silico analyses that in turn directed the identification of numerous genes with interesting chemotherapeutic characteristics, including a large family of calpain-related proteins, in which to date 23 genes were assigned as calpains in T. brucei, 40 in T. cruzi and 33 in L. braziliensis. In the present review, we intend to add to these biochemical/biological reports the investigations performed upon the inhibitory capability of calpain inhibitors against human pathogenic trypanosomatids.
To cite this article: Craig TJ, Bewtra AK, Bahna SL, Hurewitz D, Schneider LC, Levy RJ, Moy JN, Offenberger J, Jacobson KW, Yang WH, Eidelman F, Janss G, Packer FR, Rojavin MA, Machnig T, Keinecke ...H‐O, Wasserman RL. C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks – final results of the I.M.P.A.C.T.2 study. Allergy 2011; 66: 1604–1611.
Background: The placebo‐controlled study International Multicentre Prospective Angioedema C1‐INH Trial 1 (I.M.P.A.C.T.1) demonstrated that 20 U/kg C1 esterase inhibitor (C1‐INH) concentrate (Berinert®; CSL Behring, Marburg, Germany) is effective in treating acute abdominal and facial Hereditary Angioedema (HAE) attacks.
Methods: I.M.P.A.C.T.2 was an open‐label extension study of I.M.P.A.C.T.1 to evaluate the safety and efficacy of long‐term treatment with 20 U/kg C1‐INH for successive HAE attacks at any body location. Efficacy outcomes included patient‐reported time to onset of symptom relief (primary) and time to complete resolution of all symptoms (secondary), analysed on a per‐patient and per‐attack basis. Safety assessments included adverse events, vital signs, viral safety and anti‐C1‐INH antibodies.
Results: During a median study duration of 24 months, 1085 attacks were treated in 57 patients (10–53 years of age). In the per‐patient analysis, the median time to onset of symptom relief was 0.46 h and was similar for all types of attacks (0.39–0.48 h); the median time to complete resolution of symptoms was 15.5 h (shortest for laryngeal attacks: 5.8 h; 12.8–26.6 h for abdominal, peripheral and facial attacks). Demographic factors, type of HAE, intensity of attacks, time to treatment, use of androgens and presence of anti‐C1‐INH antibodies had no clinically relevant effect on the efficacy outcomes. There were no treatment‐related safety concerns. No inhibitory anti‐C1‐INH antibodies were detected in any patient.
Conclusions: A single dose of 20 U/kg C1‐INH concentrate is safe and provides reliable efficacy in the long‐term treatment of successive HAE attacks at any body location.
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Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still ...die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.
•It provides recommendations for risk reduction and screening in hereditary breast and ovarian cancer syndrome.•It focuses on risk reduction and screening mainly in unaffected carriers and ...high-resource settings.•The panel encompasses an international multidisciplinary group of experts.•Recommendations are based on available scientific data and the authors’ collective expert opinion.
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