Lessons learned from the financial crisis for financial stability and banking supervision

The financial crisis that began in 2007 has revealed a need for a new supervisory and regulatory approach aimed at strengthening the system and containing the risk of future financial and economic disruptions. Three ingredients are needed to ensure financial stability: robust analysis, better regulation, and international cooperation. First, financial stability analysis must be improved to take full account of the different sources of systemic risk. Data coverage of the balance sheets of both non-bank financial institutions and the non-financial sectors should be increased. Moreover, to address the problems raised by the interconnections among financial institutions more granular and timely information on their exposures is needed. There must be further integration of macro- and micro-information and an upgrading of financial stability models. The second ingredient is the design of robust regulatory measures. Under the auspices of the G20 and the Financial Stability Board, the Basel Committee on Banking Supervision recently put forward substantial proposals on capital and liquidity. They will result in more robust capital base, lower leverage, less cyclical capital rules and better control of liquidity risk. Finally, the third ingredient is strong international cooperation. Ensuring more effective exchanges of information among supervisors in different jurisdictions and successful common actions is key in preserving financial integration, while avoiding negative cross-border spill-overs. Better resolution regimes are part of the efforts to ensure that the crisis of one institution does not impair the ability of the financial markets to provide essential services to the economy.financial crisis, international cooperation, macroprudential analysis, procyclicality, prudential regulation, stress tests

The Role of Metals in the Neuroregenerative Action of BDNF, GDNF, NGF and Other Neurotrophic Factors

Mature neurotrophic factors and their propeptides play key roles ranging from the regulation of neuronal growth and differentiation to prominent participation in neuronal survival and recovery after injury. Their signaling pathways sculpture neuronal circuits during brain development and regulate adaptive neuroplasticity. In addition, neurotrophic factors provide trophic support for damaged neurons, giving them a greater capacity to survive and maintain their potential to regenerate their axons. Therefore, the modulation of these factors can be a valuable target for treating or preventing neurologic disorders and age-dependent cognitive decline. Neuroregenerative medicine can take great advantage by the deepening of our knowledge on the molecular mechanisms underlying the properties of neurotrophic factors. It is indeed an intriguing topic that a significant interplay between neurotrophic factors and various metals can modulate the outcome of neuronal recovery. This review is particularly focused on the roles of GDNF, BDNF and NGF in motoneuron survival and recovery from injuries and evaluates the therapeutic potential of various neurotrophic factors in neuronal regeneration. The key role of metal homeostasis/dyshomeostasis and metal interaction with neurotrophic factors on neuronal pathophysiology is also highlighted as a novel mechanism and potential target for neuronal recovery. The progress in mechanistic studies in the field of neurotrophic factor-mediated neuroprotection and neural regeneration, aiming at a complete understanding of integrated pathways, offers possibilities for the development of novel neuroregenerative therapeutic approaches

New Insight in Copper-Ion Binding to Human Islet Amyloid: The Contribution of Metal-Complex Speciation To Reveal the Polypeptide Toxicity

Type-2 diabetes (T2D) is considered to be a potential threat on a global level. Recently, T2D has been listed as a misfolding disease, such as Alzheimer's and Parkinson's diseases. Human islet amyloid polypeptide (hIAPP) is a molecule cosecreted in pancreatic β cells and represents the main constituent of an aggregated amyloid found in individuals affected by T2D. The trace-element serum level is significantly influenced during the development of diabetes. In particular, the dys-homeostasis of Cu2+ ions may adversely affect the course of the disease. Conflicting results have been reported on the protective role played by complex species formed by Cu2+ ions with hIAPP or its peptide fragments in vitro. The histidine (His) residue at position 18 represents the main binding site for the metal ion, but contrasting results have been reported on other residues involved in metal-ion coordination, in particular those toward the N or C terminus. Sequences that encompass regions 17–29 and 14–22 were used to discriminate between the two models of the hIAPP coordination mode. Due to poor solubility in water, poly(ethylene glycol) (PEG) derivatives were synthesized. A peptide fragment that encompasses the 17–29 region of rat amylin (rIAPP) in which the arginine residue at position 18 was substituted by a histidine residue was also obtained to assess that the PEG moiety does not alter the peptide secondary structure. The complex species formed by Cu2+ ions with Ac-PEG-hIAPP(17–29)-NH2, Ac-rIAPP(17–29)R18H-NH2, and Ac-PEG-hIAPP(14–22)-NH2 were studied by using potentiometric titrations coupled with spectroscopic methods (UV/Vis, circular dichroism, and EPR). The combined thermodynamic and spectroscopic approach allowed us to demonstrate that hIAPP is able to bind Cu2+ ions starting from the His18 imidazole nitrogen atom toward the N-terminus domain. The stability constants of copper(II) complexes with Ac-PEG-hIAPP(14–22)-NH2 were used to simulate the different experimental conditions under which aggregate formation and oxidative stress of hIAPP has been reported. Speciation unveils: 1) the protective role played by increased amounts of Cu2+ ions on the hIAPP fibrillary aggregation, 2) the effect of adventitious trace amounts of Cu2+ ions present in phosphate-buffered saline (PBS), and 3) a reducing fluorogenic probe on H2O2 production attributed to the polypeptide alone

Targeting mGlu5 metabotropic glutamate receptors in the treatment of cognitive dysfunction in a mouse model of phenylketonuria

We studied group-I metabotropic glutamate (mGlu) receptors in Pah(enu2) (ENU2) mice, which mimic the genetics and neurobiology of human phenylketonuria (PKU), a metabolic disorder characterized, if untreated, by autism, and intellectual disability (ID). Male ENU2 mice showed increased mGlu5 receptor protein levels in the hippocampus and corpus striatum (but not in the prefrontal cortex) whereas the transcript of the mGlu5 receptor was unchanged. No changes in mGlu1 receptor mRNA and protein levels were found in any of the three brain regions of ENU2 mice. We extended the analysis to Homer proteins, which act as scaffolds by linking mGlu1 and mGlu5 receptors to effector proteins. Expression of the long isoforms of Homer was significantly reduced in the hippocampus of ENU2 mice, whereas levels of the short Homer isoform (Homer 1a) were unchanged. mGlu5 receptors were less associated to immunoprecipitated Homer in the hippocampus of ENU2 mice. The lack of mGlu5 receptor-mediated long-term depression (LTD) in wild-type mice (of BTBR strain) precluded the analysis of hippocampal synaptic plasticity in ENU2 mice. We therefore performed a behavioral analysis to examine whether pharmacological blockade of mGlu5 receptors could correct behavioral abnormalities in ENU2 mice. Using the same apparatus we sequentially assessed locomotor activity, object exploration, and spatial object recognition (spatial novelty test) after displacing some of the objects from their original position in the arena. Systemic treatment with the mGlu5 receptor antagonist, MPEP (20 mg/kg, i.p.), had a striking effect in the spatial novelty test by substantially increasing the time spent in exploring the displaced objects in ENU2 mice (but not in wild-type mice). These suggest a role for mGlu5 receptors in the pathophysiology of ID in PKU and suggest that, also in adult untreated animals, cognitive dysfunction may be improved by targeting these receptors with an appropriate therapy

Soft drinks and sweeteners intake: Possible contribution to the development of metabolic syndrome and cardiovascular diseases. Beneficial or detrimental action of alternative sweeteners?

Abstract The rapid increase in obesity, metabolic syndrome, and cardiovascular diseases (CVDs) has been related to the rise in sugar-added foods and sweetened beverages consumption. An interesting approach has been to replace sugar with alternative sweeteners (AS), due to their impact on public health. Preclinical and clinical studies, which analyze the safety of AS intake, are still limited. Major pathogenic mechanisms of these substances include ROS and AGEs formation. Indeed, endothelial dysfunction involving in the pathogenesis of micro- and macro-vascular diseases is mitochondrial dysfunction dependent. Hyperglycemia and endoplasmic reticulum stress together produce ROS, contributing to the development and progression of cardiovascular complications during type 2 diabetes (T2D), thus causing oxidative changes and direct damage of lipids, proteins, and DNA. Epidemiological studies in healthy subjects have suggested that the consumption of artificial AS can promote CV complications, such as glucose intolerance and predisposition to the onset of T2D, whereas natural AS could reduce hyperglycemia, improve lipid metabolism and have antioxidant effects. Long-term prospective clinical randomized studies are needed to evaluate precisely whether exposure to alternative sugars can have clinical implications on natural history and clinical outcomes, especially in children or during the gestational period through breast milk

The Inorganic Side of NGF: Copper(II) And Zinc(II) Affect the NGF Mimicking Signalling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor

The nerve growth factor (NGF) N-terminus peptide, NGF(1-14), and its acetylated form, Ac-NGF(1-14), were investigated to scrutinise the ability of this neurotrophin domain to mimic the whole protein. Theoretical calculations demonstrated that non-covalent forces assist the molecular recognition of TrkA receptor for both peptides. Combined parallel tempering/docking simulations discriminated the effect of the N-terminal acetylation on the recognition of NGF(1-14) towards the domain 5 of TrkA (TrkA-D5). Experimental findings demonstrated that both NGF(1-14) and Ac-NGF(1-14) activate TrkA signaling pathways essential for neuronal survival. The NGF-induced TrkA internalization was slightly inhibited in the presence of Cu2+ and Zn2+ ions, whereas the metal ions elicited the NGF(1-14)-induced internalization of TrkA and no significant differences were found in the weak Ac-NGF(1-14)-induced receptor internalization. The crucial role of the metals was confirmed by experiments with the metal-chelator bathocuproine disulfonic acid, which discriminated different levels of inhibitory effects in the signalling cascade, due to different metal affinity of NGF, the free amino and the acetylated peptides. The NGF signaling cascade, activated by NGF (1−14) and Ac-NGF(1-14), induced CREB phosphorylation, but the copper addition further stimulated the Akt, ERK and CREB phosphorylation only for NGF and NGF(1-14). A dynamic and quick influx of both peptides into PC12 cells was tracked by live cell imaging with confocal microscopy. A significant role of copper ions was found in the modulation of peptide sub-cellular localization, especially at the nuclear level. Furthermore, a strong copper ionophoric ability of NGF(1-14) was measured. The Ac-NGF(1-14) peptide, which binds copper ions with a lower stability constant than NGF(1-14), exhibited a lower nuclear localization with respect to the total cellular uptake. These findings were correlated to the metal-induced increase of CREB and BDNF expression upon NGF(1-14) stimulation. In summary, we here validate NGF(1-14) and Ac-NGF(1-14) as first examples of monomer and linear peptides able to activate the NGF-TrkA signaling cascade. Metal ions modulate the activity of both NGF protein and the NGF-mimicking peptides. Such findings demonstrate that NGF(1-14) sequence can reproduce the signal transduction of whole protein, therefore represent a very promising drug candidate for further preclinical studies

Adhesion to and biofilm formation on IB3-1 bronchial cells by Stenotrophomonas maltophilia isolates from cystic fibrosis patients

<p>Abstract</p> <p>Background</p> <p><it>Stenotrophomonas maltophilia </it>has recently gained considerable attention as an important emerging pathogen in cystic fibrosis (CF) patients. However, the role of this microorganism in the pathophysiology of CF lung disease remains largely unexplored. In the present study for the first time we assessed the ability of <it>S. maltophilia </it>CF isolates to adhere to and form biofilm in experimental infection experiments using the CF-derived bronchial epithelial IB3-1cell line. The role of flagella on the adhesiveness of <it>S. maltophilia </it>to IB3-1 cell monolayers was also assessed by using <it>fliI </it>mutant derivative strains.</p> <p>Results</p> <p>All <it>S. maltophilia </it>CF isolates tested in the present study were able, although at different levels, to adhere to and form biofilm on IB3-1 cell monolayers. Scanning electron and confocal microscopy revealed <it>S. maltophilia </it>structures typical of biofilm formation on bronchial IB3-1 cells. The loss of flagella significantly (P < 0.001) decreased bacterial adhesiveness, if compared to that of their parental flagellated strains. <it>S. maltophilia </it>CF isolates were also able to invade IB3-1 cells, albeit at a very low level (internalization rate ranged from 0.01 to 4.94%). Pre-exposure of IB3-1 cells to <it>P. aeruginosa </it>PAO1 significantly increased <it>S. maltophilia </it>adhesiveness. Further, the presence of <it>S. maltophilia </it>negatively influenced <it>P. aeruginosa </it>PAO1 adhesiveness.</p> <p>Conclusions</p> <p>The main contribution of the present study is the finding that <it>S. maltophilia </it>is able to form biofilm on and invade CF-derived IB3-1 bronchial epithelial cells, thus posing a rationale for the persistence and the systemic spread of this opportunistic pathogen in CF patients. Experiments using <it>in vivo </it>models which more closely mimic CF pulmonary tissues will certainly be needed to validate the relevance of our results.</p

Prevalence of Asymptomatic SARS-CoV-2 Infection in the General Population of the Veneto Region: Results of a Screening Campaign with Third-Generation Rapid Antigen Tests in the Pre-Vaccine Era

The aim of our study was to ascertain the prevalence of SARS-CoV-2 infection in the general population during a period of moderate risk, just before Italy started to implement its vaccination campaign. A third-generation antigenic nasal swab sample was collected by a healthcare provider, and all individuals testing positive subsequently had a nasopharyngeal swab for molecular testing; the result was used to calculate the positive predictive value. The population consisted of 4467 asymptomatic adults with a mean age of 46.8 +/- 16.00 years. The 62.2% tested for the first time, while 37.8% had previously undergone a mean 2.2 tests for SARS-CoV-2. With 77 of our overall sample reporting they had previously tested positive for COVID-19 and 14 found positive on our screening test, the overall estimated prevalence of the infection was 0.31%. Nine of the 14 cases were confirmed on molecular testing with a PPV of 64.3%. The mean age of the individuals testing positive was 38.1 +/- 17.4. Based on the timing of symptom onset, six of the above cases were classified as false negatives, and the adjusted estimated prevalence was 0.34%. Describing levels of infection in a general population seems to be very difficult to achieve, and the universal screening proved hugely expensive particularly in a low-prevalence situation. Anyway, it is only thanks to mass screening efforts that epidemiological data have been collected. This would support the idea that routine screening may have an impact on mitigating the spread of the virus in higher-risk environments, where people come into contact more frequently, as in the workplace

Subsidence due to peatland oxidation in the Venice Lagoon catchment

Abstract. The Venice Lagoon is characterized by a fast morphodynamics appreciable not only over the geological scale but also in historical and modern times. The lagoon environment proves very sensitive to even minor modifications of the natural and anthropogenic controlling factors. An important human endeavor accomplished in the past century is the reclamation of the southernmost lagoon area that has been turned into a fertile farmland. The reclaimed soil is reach in organic matter (peat) that may oxidize with release of carbon dioxide to the atmosphere. The continuous loss of carbon is causing a pronounced settlement of the farmland that lies below the present sea/lagoon level. This enhances the flood hazard and impacts noticeably on the maintenance and operational costs of the drainage system. Total peatland subsidence is estimated at 1.5 m over the last 70 years with a current rate of 1.5-2 cm/year. The geochemical reaction is primarily controlled by soil water content and temperature, and is much influenced by agricultural practices, crop rotation, and depth to the water table. A small (24 km2) controlled catchment located in the area has been instrumented for accurately monitoring the basic parameters and recording the ground motion. The in situ measurements have been integrated with the combined use of remote sensing data to help cast light on the process and identify the mitigation strategies.Published81-906A. Monitoraggio ambientale, sicurezza e territorioope

Optimizing Fat Grafting Using a Hydraulic System Technique for Fat Processing: A Time and Cost Analysis

Background- Many authors have researched ways to optimize fat grafting by looking for a technique that offers safe and long-term fat survival rate. To date, there is no standardized protocol. We designed a “hydraulic system technique” optimizing the relationship among the quantity of injected fat, operative time, and material cost to establish fat volume cutoffs for a single procedure. Methods- Thirty-six patients underwent fat grafting surgery and were organized into three groups according to material used: standard, “1-track,” and “2-tracks” systems. The amount of harvested and grafted fat as well as material used for each procedure was collected. Operating times were recorded and statistical analysis was performed to establish the relationship with the amount of treated fat. Results- In 15 cases the standard system was used (mean treated fat 72 [30–100] mL, mean cost 4.23 ± 0.27 euros), in 11 cases the “1-track” system (mean treated fat 183.3 [120–280] mL, mean cost 7.63 ± 0.6 euros), and in 10 cases the “2-tracks” one (mean treated fat 311[220–550] mL, mean cost 12.47 ± 1 euros). The mean time difference between the standard system and the “1-track” system is statistically significant starting from three fat syringes (90 mL) in 17.66 versus 6.87 minutes. The difference between the “1-track” system and “2-tracks” system becomes statistically significant from 240 mL of fat in 15 minutes (“1-track”) versus 9.3 minutes for the “2-tracks” system. Conclusion- Data analysis would indicate the use of the standard system, “1-track,” and “2-tracks” to treat an amount of fat < 90 mL of fat, 90 ÷ 240 mL of fat, and ≥ 240 mL of fat, respectively