A Practical Guide to the Automated Analysis of Vascular Growth, Maturation and Injury in the Brain

The distinct organization of the brain’s vasculature ensures the adequate delivery of oxygen and nutrients during development and adulthood. Acute and chronic pathological changes of the vascular system have been implicated in many neurological disorders including stroke and dementia. Here, we describe a fast, automated method that allows the highly reproducible, quantitative assessment of distinct vascular parameters and their changes based on the open source software Fiji (ImageJ). In particular, we developed a practical guide to reliably measure aspects of growth, repair and maturation of the brain’s vasculature during development and neurovascular disease in mice and humans. The script can be used to assess the effects of different external factors including pharmacological treatments or disease states. Moreover, the procedure is expandable to blood vessels of other organs and vascular in vitro models. © Copyright © 2020 Rust, Kirabali, Grönnert, Dogancay, Limasale, Meinhardt, Werner, Laviña, Kulic, Nitsch, Tackenberg and Schwab

Opinion statement ECJ-TF 3/2022 on the EFTA court decision of 1 June 2022 in Case E-3/21, PRA Group Europe, on the discriminatory interaction between the "interest barrier" and group contributions

This is an Opinion Statement prepared by the CFE ECJ Task Force on the PRA Group Europe case, in which the EFTA Court delivered its decision on 1 June 2022. At issue in PRA Group Europe was the interaction of the Norwegian "interest barrier rule" ("interest limitation rule"), which generally limit the deductibility of interest payments to affiliated resident and non-resident entities to 30% of EBITDA, and the group contribution rules, which permit tax effective transfers between group members, but are limited to Norwegian entities. As group contributions also increase the EBITDA of the recipient Norwegian entity (and decrease it at the level of the paying Norwegian entity), companies in the Norwegian tax group can achieve interest deductions under the interest barrier rules where profits ("tax EBITDA") and interest expenses are distributed unevenly between the companies in the group, while a similar opportunity to escape (or lessen the impact of) the interest barrier rules is not available to cross-border groups. The EFTA Court took a combined perspective on the interaction of those rules and found them to constitute an unjustified restriction of the freedom of establishment under Articles 31 and 34 of the EEA Agreement. The EFTA Court's decision is particularly interesting from an EU law perspective, as the interest barrier rule of Article 4 of the Anti-Tax Avoidance Directive (ATAD) similarly foresees the option for Member States to introduce a domestically-limited "interest barrier group" to permit a calculation of exceeding borrowing costs and the EBITD at the local group level. The CFE ECJ Task Force welcomes the EFTA Court's progressive impetus on fundamental freedoms doctrine: PRA Group Europe AS makes it clear that for purposes of identifying a restriction, for establishing comparability and for justification, a combined perspective on the interaction of two sets of rules – here the interest barrier on the one hand and the group contribution regime on the other – is necessary. From that perspective, the interaction of the Norwegian rules on the "interest barrier" and on group contributions leads to unjustified discrimination in cross-border situations. However, if asked to decide on a similar case, the CJEU might take a different approach. First, the CJEU could take a different perspective on the available grounds of justifications and, e.g., accept the coherence of the tax system as such ground. Second, Article 4 ATAD gives the Member States the option to treat an "interest barrier group" as a single taxpayer and to limit the group perspective to domestic settings. Even if such an option in the ATAD is not viewed as "exhaustive harmonization", one could wonder if the mere existence of the ATAD and the value judgments made by the EU legislature therein could lead to a different outcome in the EU (CJEU) vis-à-vis the EEA (EFTA Court).info:eu-repo/semantics/submittedVersio

Opinion Statement ECJ-TF 2/2021 on the CJEU decision of 25 february 2021 in case C-403/19, société générale, on the calculation of the maximum amount of a foreign direct tax credit

The Court’s judgment in Société Générale reinforces the established case law that EU law neither prohibits juridical double taxation as such nor does it put an obligation on the residence Member State to prevent the disadvantages which could arise from the exercise of competence thus attributed by the two Member States. The parallel existence of taxing jurisdiction, however, must be distinguished from the exercise of such jurisdiction by each Member State: While Member States are free to determine the connecting factors for the allocation of fiscal jurisdiction in tax treaties, “the exercise of the power of taxation, so allocated by bilateral conventions for the avoidance of double taxation, the Member States must comply with EU rules and, more particularly, observe the principle of equal treatment”. It is generally accepted in the Court’s case law that both the ordinary credit and exemption (also with progression) are permissible methods to avoid double taxation, and the Court in Société Générale has confirmed this position specifically with regard to the “maximum deduction” in the ordinary credit method in tax treaties, even though it can result in a disadvantage for cross-border income as compared with domestic income. As the disadvantage in Société Générale was due to the difference between gross-basis taxation of dividends in the source Member States (Italy, the Netherlands and the UK) and net-basis taxation of those foreign-source dividends in the residence State (France), it remains to be seen if future cases will bring clarity in light of the EFTA-Court’s Seabrokers judgment as to which expenses can be lawfully allocated to foreign income from the perspective of the residence Member State. The CFE Tax Advisers Europe stresses that in an Internal Market neither (unintended) double non-taxation nor double taxation is acceptable. It therefore calls on all EU institutions to analyze and address the remaining issues of juridical double taxation (including in the context of the upcoming actions amending current corporate tax directives).info:eu-repo/semantics/publishedVersio

Opinion Statement ECJ-TF 1/2022 on the CJEU Decision of 25 November 2021 in case C-437/19, état luxembourgeois v L, on the conditions for information requests and taxpayer remedies

The CFE Tax Advisers Europe welcomes the judgment of the Court as it provides further clarification on the legal protection of the information holders afforded by Article 47 of the Charter of Fundamental Rights of the European Union in cases of cross-border exchange of information. Article 47 of the Charter guarantees that national courts can review the cross-border information request in order to assess its legality and also that the information holder must be able to ascertain the reasons upon which the order they receive is based. Moreover, the CFE Tax Advisers Europe welcomes the illumination regarding the concept of “foreseeable relevance”, but also notes that additional clarification will be needed to distinguish permissible group requests from illegal “fishing expeditions”.info:eu-repo/semantics/publishedVersio

Opinion statement ECJ-TF 3/2021 on the CJEU decision of 18 March 2021 in case C-388/19, MK v Autoridade Tributária e Aduaneira, on the taxpayers’ option to avoid discriminatory taxation of capital gains

The CFE welcomes the judgment as it clearly refers to a case of unjustified discrimination. However, there are some questions that are left open (and that Court was not required to provide an answer). The Court’s judgment in MK reinforces the established case law that EU law prohibits the adoption of non-EU compliant regimes, even if they are offered as an option to fully EU-compliant regimes. Member States are still free to adopt optional regimes but have to ensure that each one of the routes that the taxpayer may elect does not lead to unfavourable tax treatment. The CFE stresses, however, that the creation of EU-compliant options should not necessarily imply that Member States simply extend the rules conceived for residents to non-residents, as such extension may be quite both burdensome and disproportional. The CFE notes that MK may lead Member States to adopt simplified rules that end up treating non-residents more favourably. Which should not be regarded as a matter of unfairness, taking into account that they will normally be again subject to taxation at the Residence Member State, which is(traditionally) the one placed in the best position to assess a taxpayer’s ability to pay and their corresponding final tax burden.info:eu-repo/semantics/publishedVersio

Opinion statement ECJ-TF 4/2022 on the ECJ decision of 22 September 2022 in case C-538/20, W AG, on the deductibility of foreign final losses

In this CFE Opinion Statement, submitted to the EU Institutions in November 2022, the CFE ECJ Task Force comments on the ECJ decision of 22 September 2022 in W AG (Case C-538/20), on the deductibility of foreign final losses. The W AG decision makes it clear that comparability should be examined differently depending on whether the exemption is granted by domestic or tax treaty law. The CFE ECJ Task Force has reservations regarding this distinction. For the taxpayer, an exemption has the same economic effects regardless of whether it is adopted through domestic law or tax treaty law. Moreover, W AG departs from the Court’s reasoning and thinking in Lidl Belgium, which also concerned Germany and the same rules. Ideally, the Court should have made this explicit. Finally, it remains to be seen whether Marks and Spencer (Case C-446/03) is still “good law” or if W AG was one of the final nails in the coffin of the “final loss” doctrine.info:eu-repo/semantics/submittedVersio

Phenocopy – A Strategy to Qualify Chemical Compounds during Hit-to-Lead and/or Lead Optimization

A phenocopy is defined as an environmentally induced phenotype of one individual which is identical to the genotype-determined phenotype of another individual. The phenocopy phenomenon has been translated to the drug discovery process as phenotypes produced by the treatment of biological systems with new chemical entities (NCE) may resemble environmentally induced phenotypic modifications. Various new chemical entities exerting inhibition of the kinase activity of Transforming Growth Factor β Receptor I (TGF-βR1) were qualified by high-throughput RNA expression profiling. This chemical genomics approach resulted in a precise time-dependent insight to the TGF-β biology and allowed furthermore a comprehensive analysis of each NCE's off-target effects. The evaluation of off-target effects by the phenocopy approach allows a more accurate and integrated view on optimized compounds, supplementing classical biological evaluation parameters such as potency and selectivity. It has therefore the potential to become a novel method for ranking compounds during various drug discovery phases

Efficacy of imidacloprid + moxidectin and selamectin topical solutions against the KS1 Ctenocephalides felis flea strain infesting cats

<p>Abstract</p> <p>Background</p> <p>Two studies were conducted to evaluate and compare the efficacy of imidacloprid + moxidectin and selamectin topical solutions against the KS1 flea strain infesting cats. In both studies the treatment groups were comprised of non-treated controls, 6% w/v selamectin (Revolution^®; Pfizer Animal Health) topical solution and 10% w/v imidacloprid + 1% w/v moxidectin (Advantage <it>Multi</it>^®for Cats, Bayer Animal Health) topical solution. All cats were infested with 100 fleas on Days -2, 7, 14, 21, and 28. The difference in the studies was that in study #1 efficacy evaluations were conducted at 24 and 48 hours post-treatment or post-infestation, and in study #2 evaluations were conducted at 12 and 24 hours.</p> <p>Results</p> <p>In study #1 imidacloprid + moxidectin and the selamectin formulation provided 99.8% and 99.0% efficacy at 24 hours post-treatment. On day 28, the 24 hour efficacy of the selamectin formulation dropped to 87.1%, whereas the imidacloprid + moxidectin formulation provided 98.9% efficacy. At the 48 hour assessments following the 28 day infestations, efficacy of the imidacloprid + moxidectin and selamectin formulations was 96.8% and 98.3% respectively. In study # 2 the efficacy of the imidacloprid + moxidectin and selamectin formulations 12 hours after treatment was 100% and 69.4%, respectively. On day 28, efficacy of the imidacloprid + moxidectin and selamectin formulations 12 hours after infestation was 90.2% and 57.3%, respectively. In study #2 both formulations provided high levels of efficacy at the 24 hour post-infestation assessments, with selamectin and imidacloprid + moxidectin providing 95.3% and 97.5% efficacy, following infestations on day 28.</p> <p>Conclusions</p> <p>At the 24 and 48 hour residual efficacy assessments, the imidacloprid + moxidectin and selamectin formulations were similarly highly efficacious. However, the imidacloprid + moxidectin formulation provided a significantly higher rate of flea kill against the KS1 flea strain infesting cats at every 12 hour post-infestation residual efficacy assessment. Both formulations should provide excellent flea control for an entire month on cats.</p

Commentaire ECJ TF 2/2021 de la décision de la CJUE du 20 janvier 2021 dans l'affaire Lexel AB (C-484/19) concernant l'application des règles suédoises de déductibilité des intérêts

peer reviewedThis CFE Opinion Statement, submitted to the EU Institutions on 9 April 2021, addresses the decision of the Court of Justice of the European Union (First Chamber) (ECJ) of 20 January 2021 in Lexel AB (Case C-484/19).  SE: ECJ, 20 Jan. 2021, Case C-484/19, Lexel AB v. Skatteverket, Case Law IBFD. The ECJ gave its decision without an Opinion of an Advocate General. The case concerned the application of the Swedish interest deductibility rules