B-assessment, provided insights into the problems and challenges faced by the regulatory authorities and described new research concepts and their regulatoryimplications. In brief, the use of the standard BCF test following OECD TG 305 has been demonstrated to gen- erate reliable results with aquatic exposure for the major- ity of neutral, lipophilic organic substances. In addition, using column generated concentrations and keeping the total organic carbon in the test system as low as possi- ble, flow-through tests can be also carried out with highly lipophilic test items (HOCs)SPME measurements used for the extraction of freely dissolved concentrations can provide important insights into the presence of mol- ecules bound to organic matter and thus the bioavail- ability of HOCs in flow-through tests. Consequently the recommendation of SPME for measuring aqueous HOC concentrations has been included in the revised OECD TG 305. The elimination half-life (EL0.5) might be con- sidered as a potential metric which could harmonise the different bioaccumulation metrics. The prediction of bio- accumulation by in vitro approaches such as fish S9 liver fractions and primary hepatocytes shows high potential to reduce the need for animal testing. Alternatively, bio- concentration studies with the freshwater invertebrate H. azteca may support animal welfare considerations using a non-vertebrate species. Physiologically based toxicokinetic (PBTK) models can improve the under- standing of the underlying mechanisms bioaccumulation processes and reduce uncertainty of regulatory decision in the future. Organism–water and tissue–water parti- tioning coefficients for many neutral chemicals can be accurately predicted by combination of compositional information and PP-LFER models. In contrast, sorption of ions is complex and still not well understood. The use of the model COSMOmic in combination with optimised membrane dipole potentials is recommended for charged compounds. The use of new screening criteria for non- lipid accumulating substances may help to identify such compounds which pose a risk for bioaccumulation. The acquisition of information on bioaccumulation/biomag- nification potential and the mechanisms involved as well as the potential to reduce the need for vertebrate test- ing should be explored further at all levels, and incor- porated into a comprehensive testing and assessment strategy that goes beyond a mere bioconcentration factor. Concluding, we strongly recommend that the proposed amendments will be considered for implementation into the current and future guidance documents.
It was recognized that the approach of using RSCs as a way of dealing with aggregate risk was infeasible for cumulative risk because there were too many combinations of contaminants to which individuals in a population might be exposed. To deal with this, the regulatory community first introduced the concept of Hazard Index (HI), which was equal to the sum of the Hazard Quotients (HQ) across all applicable contaminants with the same mode and/or mechanism of action (hereafter, “mechanism”). The HQ is the ratio of the actual ADRI (average daily rate of intake) for an individual, expressed in units of the Reference Dose (RfD, in for example mg/kg-day) divided by the RfD itself. The regulatory reasoning was that individuals should not have a total exposure by all routes and to all contaminants with the same mechanism that produced an HI above 1.
Legal requirements to address prudential and conducts risks that DLT could introduce The potential regulatory barriers discussed above already show that existing legislation, such as SFD, EMIR, and CSDR, were not written with DLT in mind. Legislators were not yet aware that this technology existed and could become important for financial markets. Even if potential regulatory barriers would be eliminated and DLT systems would be operationalized, additional requirements might have to be introduced to ad- dress prudential and/or conduct risks introduced by this technology. According to Zetzsche et al. (2017), DLT systems might be secure from a technological perspective, but from a legal perspective these systems might spread risks amongst participants that were formerly concentrated with a limited number of central institutions. These new types of risks need to be formally addressed. Whether these new requirements should be part of a rulebook, soft guidelines, and/or hard law is a question that legislators, to- gether with the industry, should further reflect upon.
As a preliminary step, we have calculated the total correlations between the rate of growth of customer loans and of deposits, distinguishing between standalone banks, domestic and multinational parent banks and domestic and foreign affiliates. Table 3 shows that the average correlation between the loan and deposit growth is 0.54, and it is statistically significant at the 1 per cent level. Consistent with our Claim 1 (the support effect makes an affiliate’s lending capacity less responsive to local shocks on capital and deposits, i.e. on the availability of local funds) and Claim 2 (the substitution effect weakens the link between funds availability and lending. This is more so for banking groups operating in countries with little correlated real shocks and definitely less relevant for domestic banking groups operating in a single country), the correlation is slightly smaller than average for affiliates, and it is even smaller for foreign affiliates. Further, the correlation is even smaller for foreign affiliates located within more integrated areas, such as EMU and EU15, providing convincing evidence to Claim 4 (MBNs operating in an integrated area, both in terms of regulations and in terms of currencies, may make a more intense use of their ICMs). Only in the case of foreign affiliates located in the NMSs of Central and Eastern Europe and of the few foreign banks in Malta and Cyprus (non-EU15 countries), the correlation is significantly higher, consistent with the hypothesis that regulatory and monetary integration is an important ingredient fostering the functioning of ICMs. The correlation is higher than average also for parents, both domestic and MNBs, although it is smaller for the latter. A possible explanation is that parents are themselves very large banks composed with several dependent units (e.g. branches) and since they normally organize the ICM of the group, they smooth out the balance between loans and deposit of their affiliates, but keep on average stable their own relation between loans and deposits.
Models 1–4 all reject the null hypothesis that ρ = 0 at the 1% level, indi- cating that self-selection is statistically significant. Estimates of the selection equation indicate that firms’ decision to respond to the survey is significantly positively correlated with sales. We can see how self-selection affects estimates in Table 5. Generally speaking, the OLS estimates tend to be larger in mag- nitude and statistically more significant. For example, the coefficient on the Herfindahl–Hirschman index is insignificant under Models 2, 3, and 4, but is strongly significant under OLS. The magnitude of the coefficient under OLS is approximately three times that under other models. Similarly, foreign own- ership is significant under OLS, but becomes either insignificant (Models 3 and 4) or weakly significant (Models 1 and 2) after controlling for self-selec- tion. For all statistically significant coefficients, the OLS estimates are larger in magnitude with the exception of R&D expenditures and industry average emissions. The effect of industry average emissions (regulatory pressures) is insignificant under OLS but is significant under all other models after con- trolling for self-selection. Furthermore, the magnitude is more than twice that under OLS.
Probably the single most important regulatory issue pertaining to mobile banking concerns deposit taking. Some limitations and conditions on the taking of deposits from the public are generally justified - and in any case very unlikely to disappear 16 . But they may unnecessarily limit the benefits of mobile banking. By restricting the business of deposit taking, current regimes effectively encourage mobile operators to adapt billing arrangements to payments instead of proposing more efficient and well protected deposit facilities to their customers. Secondly, regulation reinforces aspiring mobile banks strategic dependence on incumbent financial institutions. Subsequently, this reduces the chances that mobile banks will emerge in sufficient numbers and with sufficient independence from incumbents to lead innovations in retail settlement networks. It is in this last domain, that the unique market position of mobile operators can make their biggest contribution, by providing the means to improve the dynamic efficiency of the payments market.
This section compares the level of transparency in the EU with other high-income economies. To check whether the standards are higher in the euro area and to be sure that we not picking up only changes in accession countries in the mid- 2000s, we focus on members of the euro area, and the pre-2004 member states (the EU15). Figure 2 compares the mean FRT Scores of euro- area and EU15 countries to those of other high- income countries in the sample. It illustrates that EU member states are less transparent in reporting national aggregate data to the IMF and World Bank compared to other high-income coun- tries. In Figure 3, which shows FRT scores for the euro-area countries in the sample, we can see that almost all have scores close to zero for much of the sample period. Through the mid-2000s, non- EU high-income countries offered on average more international regulatory data transparency than either euro-area or EU15 members. The reason for the discrepancy is that few European countries report non-bank financial institution Table 1: Most and least-transparent countries (based on median estimated FRT), ranked by FRT Index scores
directives was driven by local conditions in the banking system. 29 We do so using three time- varying proxies of bank’s health and profitability from the latest update of World Bank’s Financial Structure Database (Beck, Demirg¨ u¸ c-Kunt, and Levine (2000)). In columns (1)-(2) we control for banks’ overhead costs, while in (3)-(4) we control for banks’ profitability using the average value of banks’ net interest revenue as a share of total assets (the Data Appendix gives detailed variable definitions). Both measures of banking performance enter with insignificant estimates. In (5)-(6) we control for competition in the banking system with a concentration index that equals the share of the assets of three largest banks as a share of assets of all commercial banks. The coefficient is indistinguishable from zero. More importantly, controlling for structural features of the banking system has no effect on our main results. Cross-border banking activities increase significantly when countries adopt more rigid exchange rate arrangements (such as joining the euro). Moreover, international financial linkages are stronger among countries with more similar legal and regulatory rules in financial services.
regulated by miR-137 alone, but by multiple factors, e.g., other microRNAs, epigenetic mechanisms, subcellular localization, synaptic activity, medication, or other environ- mental factors. We analyzed miR-124 and miR-128, which act cooperatively with miR-137, and obtained no evidence that these two microRNAs influence the differential expres- sion of miR-137 targets. miR-124 precursor expression was not different between SCZ and control individuals and the differentially expressed miR-137 target genes may only slightly be co-regulated by miR-124 and miR-128. Only 23% of the analyzed miR-137 target genes were differen- tially expressed on the mRNA level between SCZ and control individuals. Most miR-137 targets have been inves- tigated in cancer cell lines and only 13 miR-137 target genes (including SHANK2) have been confirmed in neuronal cells; therefore, some of the confirmed targets may not be miR-137 targets in the brain. Expression of SHANK2 mRNA was not different in the DLPFC of SCZ and control individuals, which may mean that SHANK2 is not a relevant miR-137 target in the context of SCZ. However, we and others have identified neuronal miR-137 target genes which were regulated on protein [35, 36] and not on mRNA level. Therefore, we conclude that changes in mRNA expression do not reveal the full regulatory potential of miR-137. In this regard, proteomic data from postmortem human brains will be of high value for future SCZ studies.
The authors would like to thank the Animal Health Board and the Department of Conservation (DoC) for funding the regulatory studies, the Foundation for Science, Research and Technology for supporting work on the environmental fate and metabolism of 1080, and regional councils and the Department of Conservation for participation in a national water monitoring programme. In addition, we thank Drs W. Temple and M. Beasley of the National Toxicology Group at the Otago University School of Medicine; Drs J. Waters, N. Foronda and G. Durham of the Ministry of Health, Wellington; Dr J. Reeves of the Agricultural Compounds Unit, Ministry of Agriculture and Forestry; and Drs K. Fagerstone and P. Savarie of the National Wildlife Research Center, Fort Collins, USA, for their advice and assistance with study design and interpretation.
Beyond agents that directly target and inhibit TORCs, indirect suppression of mTOR function by modulation of the AMP-activated Protein Kinase (AMPK) pathway may provide an important alternative therapeutic approach . AMPK regulates mTOR signaling both directly and indirectly. This heterotrimeric protein kinase is activated by means of phosphorylation on the Thr172 site of the α-subunit due to an increased AMP:ATP ratio . Once active, AMPK phosphorylates and activates the TSC2 subunit of the TSC1/2 complex, which in turn suppresses Rheb activity, a small G-protein with regulatory functions on mTOR activation [52-54]. In addition, AMPK has been found to directly phosphorylate the Raptor subunit on Ser792, resulting in inactivation of the TORC1 complex .
Norway) currently supplying more than half the gas consumed within the EU and with projections pointing out that by 2030 internal sources will only be able to meet 25% of demand, EU desperately looks for means to secure new sources of gas supply. In this context, the Nabucco pipeline is planned to deliver gas from Caspian and Middle East regions to EU market. It runs across Turkey and then through Bulgaria, Romania and Hungary before connecting with a major gas hub in Austria. On paper, Nabucco project makes perfect sense, offering a new export route to EU markets for Caspian gas producers (Azerbaijan, Turkmenistan and Kazakhstan) as well as Iran and, in time, Iraq. The project is backed by the EU and strongly supported by the United States. Perhaps most importantly, Nabucco would completely bypass Russia. This paper addresses issues surrounding Nabucco project and their implications for European gas security.
The banking industry has been historically regulated by government authorities and central banks at the national level (Quaglia 2008). The timely implementation of new regulatory reporting requirements, different competent authorities for banking supervision at the national and supranational level, and lack of precise specifications resulted in partly redundant and non-harmonized data collection schemes, including the lack of overall data and reporting standards, have increased the reporting burden on banks (European Central Bank 2018a; Kardorf 2018; Kienecker et al. 2018; Kumar 2018) as well as for regulators (Piechocki 2016). Until recently, the reporting requirements for European banks used a template-driven approach to submit the processed data to the national or supranational competent authorities. The implementation of such a template-driven approach is partially based on different data repositories, i.e. accounting, risk, and regulatory data, facilitates the implementation of data silos, dedicated processing steps for different reports as well as manual processes such as corrects and reconciliation between different repositories (Bier et al. 2018; Broersen and Koppen 2017; European Commission and Financial Stability Financial Services and Capital Markets Union 2019; Kienecker et al. 2018; Kumar 2018). Aggravating to this, regulatory bodies in Europe have indicated that the reporting of granular data will be intensified in the future to fulfill their duties in the future (Bier et al. 2018; Cœuré and European Central Bank 2017).
Regulatory Affairs professional will work on the Drug and Drug Products, and prepare the Dossiers for the required application. CMC people will work on the Dossier preparations usually there will be filling of all the Dossier Forms. There will be different types of Forms for the Marketing Authorization Approvals in different Countries. Ex: Form: 21CFR 314.81: NDA, ANDA, AADA; Form: 21CFR 312.32: IND Applications.
Markets for financing personal, corporate and governmental activity became a central feature of economic life in the industrial and post-industrial age. During the last quarter of the twentieth century, measures of liberalization in regulatory oversight of those markets were accompanied by a heightened degree of complexity in transactions, as banks and other entities increasingly deployed a wider range of instruments and operated across national borders. A conjunction of factors related to these trends culminated in the global financial crisis (GFC) of 2007-2008 and, arguably, a continuing banking and fiscal crisis within the Eurozone. 1
To conclude, our approach decomposes protein domains into modules. Mapping annotated functional regions onto the decomposed structures illustrates that the modules characterize functional sites. We observe that most inter- modular boundary residues provide the shortcuts in the communication wires. These residues maintain the shortest pathways between all amino acids, leading to robust and effi- cient signal transmission communication networks. Func- tional specificity and regulation relies on the communication between modules. This advantageous organization has been conserved by evolution. Furthermore, due to the possible functional independence of modules, changes in boundary residues may lead to new functions or to functional altera- tions as might be needed in a changing environment. Therefore, a modular configuration might allow signaling proteins to increase their regulatory links, and to expand the range of control mechanisms either via new modular combi- nations or through modulation of inter-modular linkages. Since our results indicate that boundary residues are crucial in efficient short communication pathways, both mechanisms appear possible.
promise of nanodrugs, it is necessary to take a step back and look at the problems facing drug delivery as a whole rather than designing around only one or two obstacles. Incremental designs may not be sufficient to accomplish the task of treating cancer effectively. Instead, a revo- lution in concept is needed. Nanodrug delivery system with simple synthesis routes and high targeting/thera- peutic efficacy may point the way out. So far, there are so many publications but so few nanodrugs in cancer therapy. The uncertainty and limitation of nanodrugs in pharmacology, toxicology, immunology, large-scale manufacturing and regulatory issues make it become an important research field in nanoparticle-based tumor
In Nigeria it is unlikely that such indexes exist and where it exists, it has not received adequate relevance and may be at firm marketing level to determine sale performance through customer re-purchase. Expectedly, government regulatory institution, such as Standard Organization of Nigeria (SON), Nigeria Communication Commission (NCC) and the Nigeria Electricity Regulatory Commission (NERC) similar public regulatory institutions are supposed to come up with such indexes. This is the driving force for this paper. The main focus of this paper is therefore to determine the indicators of electricity Consumers Satisfaction in selected electricity distribution zones in Nigeria. Other objectives will include: -
define gene expression and regulatory networks at the genome level. Such recently developed systems biology approaches have revealed highly interconnected networks in which multiple regulatory factors act in combination. Interestingly, stem cells and cancer cells share some properties, notably self- renewal and a block in differentiation. Recently, several groups reported that expression signatures that are specific to ES cells are also found in many human cancers and in mouse cancer models, suggesting that these shared features might inform new approaches for cancer therapy. Here, we briefly summarize the key transcriptional regulators that contribute to the pluripotency of ES cells, the factors that account for the common gene expression patterns of ES and cancer cells, and the implications of these observations for future clinical applications.