The contribution of global aviation to anthropogenic climate forcing for 2000 to 2018.

Global aviation operations contribute to anthropogenic climate change via a complex set of processes that lead to a net surface warming. Of importance are aviation emissions of carbon dioxide (CO2), nitrogen oxides (NOx), water vapor, soot and sulfate aerosols, and increased cloudiness due to contrail formation. Aviation grew strongly over the past decades (1960-2018) in terms of activity, with revenue passenger kilometers increasing from 109 to 8269 billion km yr-1, and in terms of climate change impacts, with CO2 emissions increasing by a factor of 6.8 to 1034 Tg CO2 yr-1. Over the period 2013-2018, the growth rates in both terms show a marked increase. Here, we present a new comprehensive and quantitative approach for evaluating aviation climate forcing terms. Both radiative forcing (RF) and effective radiative forcing (ERF) terms and their sums are calculated for the years 2000-2018. Contrail cirrus, consisting of linear contrails and the cirrus cloudiness arising from them, yields the largest positive net (warming) ERF term followed by CO2 and NOx emissions. The formation and emission of sulfate aerosol yields a negative (cooling) term. The mean contrail cirrus ERF/RF ratio of 0.42 indicates that contrail cirrus is less effective in surface warming than other terms. For 2018 the net aviation ERF is +100.9 milliwatts (mW) m-2 (5-95% likelihood range of (55, 145)) with major contributions from contrail cirrus (57.4 mW m-2), CO2 (34.3 mW m-2), and NOx (17.5 mW m-2). Non-CO2 terms sum to yield a net positive (warming) ERF that accounts for more than half (66%) of the aviation net ERF in 2018. Using normalization to aviation fuel use, the contribution of global aviation in 2011 was calculated to be 3.5 (4.0, 3.4) % of the net anthropogenic ERF of 2290 (1130, 3330) mW m-2. Uncertainty distributions (5%, 95%) show that non-CO2 forcing terms contribute about 8 times more than CO2 to the uncertainty in the aviation net ERF in 2018. The best estimates of the ERFs from aviation aerosol-cloud interactions for soot and sulfate remain undetermined. CO2-warming-equivalent emissions based on global warming potentials (GWP* method) indicate that aviation emissions are currently warming the climate at approximately three times the rate of that associated with aviation CO2 emissions alone. CO2 and NOx aviation emissions and cloud effects remain a continued focus of anthropogenic climate change research and policy discussions.

Distinct cellular responses induced by saporin and a transferrin-saporin conjugate in two different human glioblastoma cell lines.

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults, with a median survival of ~12-18 months post-diagnosis. GBM usually recurs within 12 months post-resection, with poor prognosis. Thus, novel therapeutic strategies to target and kill GBM cells are urgently needed. The marked difference of tumour cells with respect to normal brain cells renders glioblastoma a good candidate for selective targeted therapies. Recent experimental strategies focus on over expressed cell surface receptors. Targeted toxins represent a new class of selective molecules composed by a potent protein toxin and a carrier ligand. Targeted toxins approaches against glioblastoma were under investigation in phase I and II clinical trials with several immunotoxins (IT)/ligand toxins such as IL4-Pseudomonas aeruginosa exotoxin A (IL4-PE, NBI-3001), tumour growth factor fused to PE38, a shorter PE variant, (TGF)alpha-TP-38, IL13-PE38, and a transferrin-C diphtheriae toxin mutant (Tf-CRM107). In this work, we studied the effects of the plant ribosome-inactivating saporin and of its chimera transferrin-saporin against two different GBM cell lines. The data obtained here indicate that cell proliferation is affected by the toxin treatments but that different mechanisms are used, directly linked to the presence of an active or inactive p53. A model is proposed for these alternative intracellular pathways.

Transport impacts on atmosphere and climate: Aviation.

Aviation alters the composition of the atmosphere globally and can thus drive climate change and ozone depletion. The last major international assessment of these impacts was made by the Intergovernmental Panel on Climate Change (IPCC) in 1999. Here, a comprehensive updated assessment of aviation is provided. Scientific advances since the 1999 assessment have reduced key uncertainties, sharpening the quantitative evaluation, yet the basic conclusions remain the same. The climate impact of aviation is driven by long-term impacts from CO2 emissions and shorter-term impacts from non-CO2 emissions and effects, which include the emissions of water vapour, particles and nitrogen oxides (NO x ). The present-day radiative forcing from aviation (2005) is estimated to be 55 mW m-2 (excluding cirrus cloud enhancement), which represents some 3.5% (range 1.3-10%, 90% likelihood range) of current anthropogenic forcing, or 78 mW m-2 including cirrus cloud enhancement, representing 4.9% of current forcing (range 2-14%, 90% likelihood range). According to two SRES-compatible scenarios, future forcings may increase by factors of 3-4 over 2000 levels, in 2050. The effects of aviation emissions of CO2 on global mean surface temperature last for many hundreds of years (in common with other sources), whilst its non-CO2 effects on temperature last for decades. Much progress has been made in the last ten years on characterizing emissions, although major uncertainties remain over the nature of particles. Emissions of NO x result in production of ozone, a climate warming gas, and the reduction of ambient methane (a cooling effect) although the overall balance is warming, based upon current understanding. These NO x emissions from current subsonic aviation do not appear to deplete stratospheric ozone. Despite the progress made on modelling aviation's impacts on tropospheric chemistry, there remains a significant spread in model results. The knowledge of aviation's impacts on cloudiness has also improved: a limited number of studies have demonstrated an increase in cirrus cloud attributable to aviation although the magnitude varies: however, these trend analyses may be impacted by satellite artefacts. The effect of aviation particles on clouds (with and without contrails) may give rise to either a positive forcing or a negative forcing: the modelling and the underlying processes are highly uncertain, although the overall effect of contrails and enhanced cloudiness is considered to be a positive forcing and could be substantial, compared with other effects. The debate over quantification of aviation impacts has also progressed towards studying potential mitigation and the technological and atmospheric tradeoffs. Current studies are still relatively immature and more work is required to determine optimal technological development paths, which is an aspect that atmospheric science has much to contribute. In terms of alternative fuels, liquid hydrogen represents a possibility and may reduce some of aviation's impacts on climate if the fuel is produced in a carbon-neutral way: such fuel is unlikely to be utilized until a 'hydrogen economy' develops. The introduction of biofuels as a means of reducing CO2 impacts represents a future possibility. However, even over and above land-use concerns and greenhouse gas budget issues, aviation fuels require strict adherence to safety standards and thus require extra processing compared with biofuels destined for other sectors, where the uptake of such fuel may be more beneficial in the first instance.

Can colorectal cancer be prevented or treated by oral hormone replacement therapy?

Guanylyl cyclase C (GCC) is the receptor specifically expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin and diarrheagenic bacterial heat-stable enterotoxins. This tissue-specific receptor coordinates lineage-dependent regulation of epithelial homeostasis, and its disruption contributes to intestinal tumorigenesis. It coordinates regenerative and metabolic circuits by restricting the cell cycle and proliferation and programming metabolic transitions central to organizing the dynamic crypt-surface axis. Further, mice deficient in GCC signaling are more susceptible to colon cancer induced by Apc mutations or the carcinogen azoxymethane. Moreover, guanylin and uroguanylin are gene products most commonly lost, early, in colon cancer in animals and humans. The role of GCC as a tumor suppressing receptor regulating proliferation and metabolism, together with the universal loss of guanylin and uroguanylin in tumorigenesis, suggests a model in which colorectal cancer is a paracrine hormone deficiency syndrome. In that context, activation of GCC reverses the tumorigenic phenotype by limiting growth of colorectal cancer cells by restricting progression through the G1/S transition and reprogramming metabolic circuits from glycolysis to oxidative phosphorylation, limiting bioenergetic support for rapid proliferation. These observations suggest a pathophysiological hypothesis in which GCC is a lineage-dependent tumor suppressing receptor coordinating proliferative homeostasis whose dysregulation through hormone loss contributes to neoplasia. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral supplementation with GCC ligands.

GCC signaling in colorectal cancer: Is colorectal cancer a paracrine deficiency syndrome?

Guanylyl cyclase C (GCC) is the receptor expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin that coordinate mucosal homeostasis and its silencing contributes to intestinal transformation. It orchestrates proliferative and metabolic circuits by limiting the cell cycle and programming metabolic transitions central to regeneration along the crypt-villus axis. Mice deficient in GCC are more susceptible to colon cancer induced by germline mutations or carcinogens. Moreover, guanylin and uroguanylin are the most commonly lost gene products in colon cancer. The role of GCC as a tumor suppressor and the universal loss of its hormones in transformation suggest a paradigm in which colorectal cancer is a disease of paracrine hormone insufficiency. Indeed, GCC signaling reverses the tumorigenic phenotype of human colon cancer cells by regulating proliferation and metabolism. These data suggest a pathophysiological hypothesis in which GCC is a tumor suppressor coordinating proliferative homeostasis whose silencing through hormone loss initiates transformation. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral hormone replacement therapy employing GCC ligands.

Colorectal cancer is a paracrine deficiency syndrome amenable to oral hormone replacement therapy.

The most commonly lost gene products in colorectal carcinogenesis include the paracrine hormones guanylin and uroguanylin, the endogenous ligands for guanylyl cyclase C (GCC), the intestinal receptor for diarrheagenic bacterial enterotoxins. Recently, GCC-cGMP signaling has emerged as a principal regulator of proliferation, genetic integrity and metabolic programming in normal human enterocytes and colon cancer cells. Elimination of GCC in mice produced hyperplasia of the proliferating compartment associated with increases in rapidly cycling progenitor cells, and reprogrammed enterocyte metabolism, with a shift from oxidative phosphorylation to glycolysis. In addition, in colons of mice carrying mutations in Apc (Apc(Min) (/+)) or exposed to the carcinogen azoxymethane, elimination of GCC increased tumor initiation and promotion by disrupting genomic integrity and releasing cell cycle restriction. These previously unrecognized roles for GCC as a fundamental regulator of intestinal homeostasis and as an intestinal tumor suppressor suggest that receptor dysregulation reflecting paracrine hormone insufficiency is a key event during the initial stages of colorectal tumorigenesis. Together with the uniform over-expression of GCC in human tumors, these novel roles for GCC underscore the potential of oral replacement with GCC ligands for targeted prevention and therapy of colorectal cancer.

The paracrine hormone hypothesis of colorectal cancer.

Colorectal carcinogenesis originates in the context of dysregulated epithelial cell homeostasis, wherein hyperproliferation, hypodifferentiation, metabolic reprogramming, and mesenchymal remodeling reflect recursive mutually reinforcing mechanisms contributing to progressive genomic instability. Although genotypic and phenotypic elements characterizing the terminal integration of these pathophysiological processes defining cancer are well enumerated, events initiating, coordinating, and sustaining this hierarchical maladaptive systems evolution remain elusive for most tumors. In the intestine, guanylyl cyclase C (GCC) and its paracrine ligands organize and regulate the homeostatic integrity of the crypt-villus axis, forming a hormonal tumor suppressor signaling sequence, whose dysfunction defines the initiation of neoplastic transformation and creates a permissive niche for tumor progression.

Double-blind, placebo-controlled homeopathic pathogenetic trials: symptom collection and analysis.

BACKGROUND: Homeopathic pathogenetic trials (provings) are fundamental to homeopathy. Since most of the data from available provings have not been statistically evaluated, it is unclear how specific reported symptoms are and how they differ from those reported by people taking placebo. METHOD: We combine and analyse data from two different homeopathic pathogenic trials--including 10 and 11 provers, respectively, and both including 30% placebo-to test the null hypothesis that there is no significant difference between the number of symptoms in placebo and verum groups. RESULTS: The principal results were: Placebo reported less symptoms than verum groups. Symptom distribution according to predefined classes (common symptoms increased in intensity and/or duration-, cured, old, new and exceptional) was statistically different between placebo and verum group at a high level of significance (P<0.001). Compared to verum, placebo provers reported less new and old but more common (increased in duration or intensity) symptoms. Within repertory categories, other differences were detected. The two groups differ in terms of the duration of each symptom and kinetics of symptoms: most symptoms were more persistent in verum than in placebo groups and verum provers recorded a decreasing number of symptoms with time. Placebo provers did not show such a temporal pattern. CONCLUSIONS: If confirmed by other studies these results would demonstrate the non-equivalence between homeopathic medicines in high dilution and placebo and contribute to the improvement of proving methodology and evaluation.

The global atmospheric environment for the next generation.

Air quality, ecosystem exposure to nitrogen deposition, and climate change are intimately coupled problems: we assess changes in the global atmospheric environment between 2000 and 2030 using 26 state-of-the-art global atmospheric chemistry models and three different emissions scenarios. The first (CLE) scenario reflects implementation of current air quality legislation around the world, while the second (MFR) represents a more optimistic case in which all currently feasible technologies are applied to achieve maximum emission reductions. We contrast these scenarios with the more pessimistic IPCC SRES A2 scenario. Ensemble simulations for the year 2000 are consistent among models and show a reasonable agreement with surface ozone, wet deposition, and NO2 satellite observations. Large parts of the world are currently exposed to high ozone concentrations and high deposition of nitrogen to ecosystems. By 2030, global surface ozone is calculated to increase globally by 1.5 +/- 1.2 ppb (CLE) and 4.3 +/- 2.2 ppb (A2), using the ensemble mean model results and associated +/-1 sigma standard deviations. Only the progressive MFR scenario will reduce ozone, by -2.3 +/- 1.1 ppb. Climate change is expected to modify surface ozone by -0.8 +/- 0.6 ppb, with larger decreases over sea than over land. Radiative forcing by ozone increases by 63 +/- 15 and 155 +/- 37 mW m(-2) for CLE and A2, respectively, and decreases by -45 +/- 15 mW m(-2) for MFR. We compute that at present 10.1% of the global natural terrestrial ecosystems are exposed to nitrogen deposition above a critical load of 1 g N m(-2) yr(-1). These percentages increase by 2030 to 15.8% (CLE), 10.5% (MFR), and 25% (A2). This study shows the importance of enforcing current worldwide air quality legislation and the major benefits of going further. Nonattainment of these air quality policy objectives, such as expressed by the SRES-A2 scenario, would further degrade the global atmospheric environment.

The effect of AZT and chloroquine on the activities of ricin and a saporin-transferrin chimeric toxin.

This study deals with the combination of chloroquine (CQ, an anti-malaric drug) and 3'-azido-3'-deoxythymidine (AZT, anti-human immuno-deficiency virus (HIV) drug) with a chimeric toxin (TS) obtained by chemical linking of saporin (a ribosome inactivating protein from the plant Saponaria officinalis) and human transferrin, in the intoxication of the human chronic myeloid leukaemia cells (K562). Our data demonstrate that AZT, at concentrations comparable to those reached in the blood of HIV-infected patients under pharmacological treatment with this drug, can increase the toxicity of TS in cooperation with CQ inducing an increased effect on protein synthesis in K562 cells ( approximately 50% inhibition of protein synthesis for TS alone, and TS with AZT and approximately 70% with both AZT and CQ). Furthermore, pre-treatment of cells with AZT alone can induce an increase of apoptosis in K562 cells intoxicated with TS. By comparing data obtained with the model toxin ricin, we get indications that the two toxins partially differ in their intracellular routes, also suggesting that chimeric constructs containing ricin-like toxins (i.e. immunotoxins) could be coupled with the use of common and cheap drugs for the treatment of cancer in HIV-infected patients.

Vanin-1-/- mice exhibit a glutathione-mediated tissue resistance to oxidative stress.

Vanin-1 is an epithelial ectoenzyme with pantetheinase activity and generating the amino-thiol cysteamine through the metabolism of pantothenic acid (vitamin B(5)). Here we show that Vanin-1(-/-) mice, which lack cysteamine in tissues, exhibit resistance to oxidative injury induced by whole-body gamma-irradiation or paraquat. This protection is correlated with reduced apoptosis and inflammation and is reversed by treating mutant animals with cystamine. The better tolerance of the Vanin-1(-/-) mice is associated with an enhanced gamma-glutamylcysteine synthetase activity in liver, probably due to the absence of cysteamine and leading to elevated stores of glutathione (GSH), the most potent cellular antioxidant. Consequently, Vanin-1(-/-) mice maintain a more reducing environment in tissue after exposure to irradiation. In normal mice, we found a stress-induced biphasic expression of Vanin-1 regulated via antioxidant response elements in its promoter region. This process should finely tune the redox environment and thus change an early inflammatory process into a late tissue repair process. We propose Vanin-1 as a key molecule to regulate the GSH-dependent response to oxidative injury in tissue at the epithelial level. Therefore, Vanin/pantetheinase inhibitors could be useful for treatment of damage due to irradiation and pro-oxidant inducers.

Guanylyl cyclase is an ATP sensor coupling nitric oxide signaling to cell metabolism.

Defending cellular integrity against disturbances in intracellular concentrations of ATP ([ATP](i)) is predicated on coordinating the selection of substrates and their flux through metabolic pathways (metabolic signaling), ATP transfer from sites of production to utilization (energetic signaling), and the regulation of processes consuming energy (cell signaling). Whereas NO and its receptor, soluble guanylyl cyclase (sGC), are emerging as key mediators coordinating ATP supply and demand, mechanisms coupling this pathway with metabolic and energetic signaling remain undefined. Here, we demonstrate that sGC is a nucleotide sensor whose responsiveness to NO is regulated by [ATP](i). Indeed, ATP inhibits purified sGC with a K(i) predicting >60% inhibition of NO signaling in cells maintaining physiological [nucleotide](i). ATP inhibits sGC by interacting with a regulatory site that prefers ATP > GTP. Moreover, alterations in [ATP](i), by permeabilization and nucleotide clamping or inhibition of mitochondrial ATP synthase, regulate NO signaling by sGC. Thus, [ATP](i) serves as a "gain control" for NO signaling by sGC. At homeostatic [ATP](i), NO activation of sGC is repressed, whereas insults that reduce [ATP](i,) derepress sGC and amplify responses to NO. Hence, sGC forms a key synapse integrating metabolic, energetic, and cell signaling, wherein ATP is the transmitter, allosteric inhibition the coupling mechanism, and regulated accumulation of cGMP the response.

Bacterial enterotoxins are associated with resistance to colon cancer.

One half million patients suffer from colorectal cancer in industrialized nations, yet this disease exhibits a low incidence in under-developed countries. This geographic imbalance suggests an environmental contribution to the resistance of endemic populations to intestinal neoplasia. A common epidemiological characteristic of these colon cancer-spared regions is the prevalence of enterotoxigenic bacteria associated with diarrheal disease. Here, a bacterial heat-stable enterotoxin was demonstrated to suppress colon cancer cell proliferation by a guanylyl cyclase C-mediated signaling cascade. The heat-stable enterotoxin suppressed proliferation by increasing intracellular cGMP, an effect mimicked by the cell-permeant analog 8-br-cGMP. The antiproliferative effects of the enterotoxin and 8-br-cGMP were reversed by L-cis-diltiazem, a cyclic nucleotide-gated channel inhibitor, as well as by removal of extracellular Ca(2+), or chelation of intracellular Ca(2+). In fact, both the enterotoxin and 8-br-cGMP induced an L-cis-diltiazem-sensitive conductance, promoting Ca(2+) influx and inhibition of DNA synthesis in colon cancer cells. Induction of this previously unrecognized antiproliferative signaling pathway by bacterial enterotoxin could contribute to the resistance of endemic populations to intestinal neoplasia, and offers a paradigm for targeted prevention and therapy of primary and metastatic colorectal cancer.

Vanin genes are clustered (human 6q22-24 and mouse 10A2B1) and encode isoforms of pantetheinase ectoenzymes.

The mouse Vanin-1 molecule plays a role in thymic reconstitution following damage by irradiation. We recently demonstrated that it is a membrane pantetheinase (EC 3.56.1.-). This molecule is the prototypic member of a larger Vanin family encoded by at least two mouse (Vanin-1 and Vanin-3) and three human (VNN1, VNN2, VNN3) orthologous genes. We now report (1) the structural characterization of the human and mouse Vanin genes and their organization in clusters on the 6q22-24 and 10A2B1 chromosomes, respectively; (2) identification of the human VNN3 gene and the demonstration that the mouse Vanin-3 molecule is secreted by cells, and (3) that the Vanin genes encode different isoforms of the mammalian pantetheinase activity. Thus, the Vanin family represents a novel class of secreted or membrane-associated ectoenzymes. We discuss here their possible role in processes pertaining to tissue repair in the context of oxidative stress.

Guanylyl cyclase C agonists regulate progression through the cell cycle of human colon carcinoma cells.

The effects of Escherichia coli heat-stable enterotoxin (ST) and uroguanylin were examined on the proliferation of T84 and Caco2 human colon carcinoma cells that express guanylyl cyclase C (GC-C) and SW480 human colon carcinoma cells that do not express this receptor. ST or uroguanylin inhibited proliferation of T84 and Caco2 cells, but not SW480 cells, in a concentration-dependent fashion, assessed by quantifying cell number, cell protein, and [(3)H]thymidine incorporation into DNA. These agonists did not inhibit proliferation by induction of apoptosis, assessed by TUNEL (terminal deoxynucleotidyl transferase-mediated dNTP-biotin nick end labeling of DNA fragments) assay and DNA laddering, or necrosis, assessed by trypan blue exclusion and lactate dehydrogenase release. Rather, ST prolonged the cell cycle, assessed by flow cytometry and [(3)H]thymidine incorporation into DNA. The cytostatic effects of GC-C agonists were associated with accumulation of intracellular cGMP, mimicked by the cell-permeant analog 8-Br-cGMP, and reproduced and potentiated by the cGMP-specific phosphodiesterase inhibitor zaprinast but not the inactive ST analog TJU 1-103. Thus, GC-C agonists regulate the proliferation of intestinal cells through cGMP-dependent mechanisms by delaying progression of the cell cycle. These data suggest that endogenous agonists of GC-C, such as uroguanylin, may play a role in regulating the balance between epithelial proliferation and differentiation in normal intestinal physiology. Therefore, GC-C ligands may be novel therapeutic agents for the treatment of patients with colorectal cancer.

Pantetheinase activity of membrane-bound Vanin-1: lack of free cysteamine in tissues of Vanin-1 deficient mice.

Pantetheinase (EC 3.5.1.-) is an ubiquitous enzyme which in vitro has been shown to recycle pantothenic acid (vitamin B5) and to produce cysteamine, a potent anti-oxidant. We show that the Vanin-1 gene encodes pantetheinase widely expressed in mouse tissues: (1) a pantetheinase activity is specifically expressed by Vanin-1 transfectants and is immunodepleted by specific antibodies; (2) Vanin-1 is a GPI-anchored pantetheinase, and consequently an ectoenzyme; (3) Vanin-1 null mice are deficient in membrane-bound pantetheinase activity in kidney and liver; (4) in these organs, a major metabolic consequence is the absence of detectable free cysteamine; this demonstrates that membrane-bound pantetheinase is the main source of cysteamine in tissues under physiological conditions. Since the Vanin-1 molecule was previously shown to be involved in the control of thymus reconstitution following sublethal irradiation in vivo, this raises the possibility that Vanin/pantetheinase might be involved in the regulation of some immune functions maybe in the context of the response to oxidative stress.

Comparison of pharmacological treatment versus acupuncture treatment for migraine without aura--analysis of socio-medical parameters.

This study was carried out in 120 patients affected by migraine without aura, treated in 4 public health centers and randomly divided into acupuncture group (AG) and conventional drug therapy group (CDTG). The evaluation of clinical results was made 6 and 12 months after the beginning of treatment and was worked out as well according to socio-medical parameters. Acupuncture was applied to the following points: Touwei (ST 8), Xuanlu (GB 5), Fengchi (GB 20), Dazhui (GV 14), Lieque (LU 7), treated with the reducing method. In AG, the figure scoring the entity and frequency of migraine attacks drops from 9,823 before treatment to 1,990 6 months after and 1,590 12 months after; while in CDTG, it drops from 8,405 before treatment to 3,927 6 months after and 3,084 12 months after. In AG, the total absence from work amounted to 1,120 working days/year, with a total cost (private + social costs) of 186,677,000 Italian liras. In CDTG, the absence from work amounted to 1,404 working days/year, with a total cost of 266,614,000 Italian liras. If we consider that in Italy the patients affected by migraine without aura are around 800,000, and that acupuncture therapy is able to save 1,332,000 Italian liras on the total average cost supported for every single patient, the application of acupuncture in the treatment of migraine without aura would allow a saving of the health expenses in Italy of over 1,000 billion liras.

Guanylyl cyclases and signaling by cyclic GMP.

Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types. They are regulated by diverse extracellular agonists that include peptide hormones, bacterial toxins, and free radicals, as well as intracellular molecules, such as calcium and adenine nucleotides. Stimulation of guanylyl cyclases and the resultant accumulation of cGMP regulates complex signaling cascades through immediate downstream effectors, including cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. Guanylyl cyclases and cGMP-mediated signaling cascades play a central role in the regulation of diverse (patho)physiological processes, including vascular smooth muscle motility, intestinal fluid and electrolyte homeostasis, and retinal phototransduction. Topics addressed in this review include the structure and chromosomal localization of the genes for guanylyl cyclases, structure and function of the members of the guanylyl cyclase family, molecular mechanisms regulating enzymatic activity, and molecular sequences coupling ligand binding to catalytic activity. A brief overview is presented of the downstream events controlled by guanylyl cyclases, including the effectors that are regulated by cGMP and the role that guanylyl cyclases play in cell physiology and pathophysiology.

Biochemical and ultrastructural alterations in rat after hyperoxic treatment: effect of taurine and hypotaurine.

The cell ultrastructure and some detoxifying enzyme activities were studied in skeletal muscles of young rats kept for 84 h under normobaric hyperoxia (95% O2) or normoxia as control. Rat were injected i.p.. Every 12 h either with 1 ml saline, 1 ml saline+30 mg hypotaurine or 1 ml saline+30 mg taurine. Ultrastructural observation revealed an highly protective effect on tissue damages due to hyperoxia in taurine-treated rats and, at less extent, in hypotaurine-treated ones. Enzymatic assays suggest a different mechanism of the two molecules in their protective action.

Hypotaurine protection on cell damage by singlet oxygen.

Singlet oxygen (1O2), generated by irradiating methylene blue, is toxic to melanoma cell cultures. Hypotaurine is known to scavenge efficiently singlet oxygen; the addition of hypotaurine (800 microM) to the medium during irradiation of the dye produces a greater protective effect on cells than taurine added at the same concentration. The assay of some detoxifying enzymatic activities indicate a different mechanism of protection of the two molecules: taurine induces an efficient detoxifying enzymatic action with respect to the control; hypotaurine exerts its effect greatly by specifically scavenging singlet oxygen.